Therapeutic agents comprising fusions of insulin and elastic peptides

ABSTRACT

The present invention provides therapeutic agents and compositions comprising elastic peptides and therapeutic proteins. Such peptides exhibit a flexible, extended conformation. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.

PRIORITY

This application is a continuation of U.S. application Ser. No.12/852,365, filed Aug. 6, 2010, which is a continuation-in-part of U.S.application Ser. No. 12/493,912, filed Jun. 29, 2009, now U.S. Pat. No.8,178,495, which claims priority to U.S. Provisional Application No.61/076,221, filed Jun. 27, 2008, each of which is hereby incorporated byreference in its entirety. U.S. application Ser. No. 12/852,365 is alsoa continuation-in-part of U.S. application Ser. No. 12/158,190, now U.S.Pat. No. 8,334,257, which is a U.S. national stage of PCT/US06/048572,filed Dec. 20, 2006, which claims priority to U.S. ProvisionalApplication No. 60/751,896, filed Dec. 20, 2005, each of which is herebyincorporated by reference in its entirety.

GOVERNMENT SUPPORT

This invention was made with Government support under grant numberEB00188 and GM-061232 from National Institutes of Health. The USGovernment has certain rights to this invention.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith areincorporated herein by reference in their entirety: A computer readableformat copy of the Sequence Listing (filename: PHAS_021_00US_SeqList_ST25.txt, date recorded: Aug. 6, 2010, file size 50 kb).

BACKGROUND OF THE INVENTION

Therapeutic proteins or peptides in their native state or whenrecombinantly produced can be labile molecules exhibiting, inter alia,short periods of serum stability, serum half-life (i.e., circulatoryhalf-life), or limited persistance in the body. Such molecules can alsobe extremely labile when formulated, such as when formulated in aqueoussolutions.

In some instances, polyethylene glycol (PEG) conjugated to aproteinaceous molecule results in a longer-acting, sustained activity ofthe molecule. PEG attachment, however, can often substantially reduce oreven destroy the protein's therapeutic activity. Therapeutic proteinsand/or peptides have also been stabilized by fusion to certain proteinsthat are capable of extending serum half-life. For example, in someinstances, therapeutic proteins fused to albumin, transferrin, andantibody fragments exhibit extended serum half-life when compared to thetherapeutic protein in the unfused state. See U.S. Pat. No. 7,238,667(particularly with respect to albumin conjugates), U.S. Pat. No.7,176,278 (particularly with respect to transferrin conjugates), andU.S. Pat. No. 5,766,883, which are each hereby incorporated by referencein their entireties.

There remains a need in the art for more stable, longer acting, and/oreffective proteinaceous molecules.

SUMMARY OF THE INVENTION

The present invention provides therapeutic agents comprising an elasticpeptide component and a therapeutic proteinacious component. The elasticpeptide component may form a spiral conformation, and/or may have anextended structure relative to an alpha helix. The elastic peptidecomponent may be structurally related to, or derived from, sequences ofthe elastin protein (elastin-like-peptide or ELP). Such elastic peptidecomponents provide certain therapeutic advantages to the therapeuticagent, such as comparatively better stability, solubility,bioavailability, half-life, persistance, and/or biological action of thetherapeutic proteinaceous component. Such properties may be determined,for example, with respect to the therapeutic component's unfused orunconjugated counterpart. In some embodiments, the elastic peptide is anELP that undergoes a reversible inverse phase transition, which mayimpart additional practical and/or therapeutic advantages. The inventionfurther provides polynucleotides encoding the therapeutic agents of theinvention, as well as methods of treatment or prophylaxis for certainbiological conditions.

In a first aspect, the invention provides a therapeutic agent comprisingan elastic peptide component and a therapeutic proteinacious component,as well as pharmaceutical compositions containing the same for deliveryto a subject or patient in need. The therapeutic component may beselected from active portions of the therapeutic proteins describedherein, including those listed in Table 1, or functional analogsthereof. In certain embodiments, the therapeutic component is a GLP-1receptor agonist, such as GLP-1, exendin-4, or a functional analogthereof. Such therapeutic components are generally effective for, amongother things, increasing insulin secretion from the pancreas in aglucose-dependent manner. In other embodiments, the therapeuticcomponent is an insulin or functional analog thereof, which is generallyeffective for promoting glucose uptake from the blood and storage withincells. In still other embodiments, the therapeutic component is a FactorVII/VIIa or functional analog thereof, which is generally effective forpromoting coagulation by activation of Factor X or Factor IX.

The elastic peptide and therapeutic components may be covalently coupledby various means, including chemical coupling (e.g., conjugation) andrecombinant fusion technology. In addition, the number of elasticpeptide or therapeutic components per molecule, and their respectivepositions within the molecule, may vary as needed. The therapeutic agentmay further include one or more spacer or linker moieties, which inaddition to providing the desired functional independence of the elasticpeptide and therapeutic components, may optionally provide foradditional functionalities, such as a protease-sensitive feature toallow for proteolytic release or activation of the therapeuticcomponent. The therapeutic agent may further include one or moretargeting components such as, for example, a peptide or protein totarget the therapeutic agent to a particular cell type, e.g., a cancercell, or to a particular organ.

In a second aspect, the invention provides polynucleotides, suchpolynucleotides comprising a nucleotide sequence encoding a therapeuticagent of the invention. For example, the nucleotide sequence encodes anelastic peptide fusion with a functional portion of at least onetherapeutic protein described herein, including those listed in Table 1(or functional analog thereof). In certain embodiments, the therapeuticcomponent is a GLP-1 receptor agonist (including GLP-1 and exendin-4),insulin, Factor VII/VIIa, or functional analog thereof. Suchpolynucleotides may further comprise additional control element(s)operably linked to the nucleotide sequence, such as promoter elementsand/or other transcription or expression-related signals. Thepolynucleotide may be inserted into various vectors, which may be usefulfor production of the therapeutic agent in host cells, including, forexample, bacterial and eukaryotic host cells.

In a third aspect, the invention provides a method for treating orpreventing a disease, disorder, or condition in a subject, such as in amammalian patient, including a human patient. The method comprisesadministering an effective amount of the therapeutic agent of theinvention (or pharmaceutical composition containing the same) to asubject or patient in need thereof. For example, the patient may be inneed of an agent having a biological activity or preferred indicationlisted herein (e.g., in Table 1). In certain embodiments employing aGLP-1 receptor agonist/elastic peptide compound or employing aninsulin/elastic peptide compound, the invention provides a method fortreating one or more disorders including type 1 or type 2 diabetes,hyperglycemia, and impaired glucose tolerance. In certain otherembodiments employing Factor VII/VIIa/elastic peptide compound, theinvention provides a method for treating one or more disorders includinghemophilia, post-surgical bleeding, anticoagulation-induced bleeding,thrombocytopenia, factor VII deficiency, factor XI deficiency, andintracranial hemorrhage.

Various other aspects, features and embodiments of the invention will bemore fully apparent from the following disclosure and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts plasmid pET24d-ELP1-90, encoding an elastin-like-peptide(ELP) component with a 10 unit VPGXG (SEQ ID NO: 3) repeat motif, whereguest position X is V, G, and A in the ratio of 5:3:2. This motif isrepeated eight times with a final C-terminal 10-unit repeat where X isV, G, A, and W in the ratio 4:3:2:1. This ELP component is representedgenerally as [(VPGXG)₁₀]₉.

FIG. 2A depicts plasmid pET24d-Ex-4 ELP1-90 encoding an ELP componentwith VPGXG (SEQ ID NO: 3) repeat motif (as in FIG. 1) cloned in framewith an N-terminal exendin-4 component. FIG. 2B depicts the nucleotideand amino acid sequence of the exendin-4/ELP fusion (SEQ ID NOS: 23 and24). Primer sequences are indicated (SEQ ID NOS:35-40).

FIG. 3A depicts the nucleotide and amino acid sequence of an exendin-4construct having an N-terminal Tev (Tobacco Etch Virus cysteineprotease) cleavage site (SEQ ID NOS: 25 and 26). Primer sequences areindicated (SEQ ID NOS:38, 41, 42). FIG. 3B also depicts the nucleotideand amino acid sequence of an exendin-4 construct having an N-terminalTev cleavage site, but with an additional sequence N-terminal to the Tevcleavage site to provide a better target for the protease (SEC) ID NOS:27 and 28). Primer sequences are indicated (SEQ ID NOS:38, 43, 44).

FIG. 4A depicts the nucleotide and amino acid sequence of anexendin-4/ELP fusion as in FIGS. 1-3, but with a DsbA leader sequence todirect secretion into the periplasmic space (SEQ ID NOS: 29 and 30).Primer sequences are indicated (SEQ ID NOS:38, 45, 46). FIG. 4B depictsplasmid pET24d-DsbA-Ex-4 ELP1-90 encoding the fusion of FIG. 4A.

FIG. 5A depicts pPB0868, which encodes GLP-1(A8G, 7-37)ELP1-90. FIG. 5Bdepicts the nucleotide and amino acid sequence of the encoded fusionprotein (SEQ ID NOS: 53 and 54, respectively).

FIG. 6A depicts pPB1022, which encodes GLP-1(A8G,7-37)ELP1-120. FIG. 6Bdepicts the nucleotide and amino acid sequence of the encoded fusionprotein (SEQ ID NOS: 55 and 56, respectively).

FIG. 7A depicts pPB0788, which encodes Factor VII-ELP1-90. FIG. 7Bdepicts the nucleotide and amino acid sequence of the encoded fusionprotein (SEQ ID NOS: 57 and 58, respectively).

FIG. 8A depicts the nucleotide and amino acid sequence of an insulin (B,C, and A chains) having the ELP component cloned in frame (SEQ ID NOS:31 and 32). Primer sequences are indicated (SEQ ID NOS: 47 and 48). FIG.8B depicts plasmid pET24d Insulin-ELP1-90 expressing the insulin/ELPfusion of FIG. 8A.

FIG. 9 is a Western blot for FVII-ELP1-90 from transient transfection ofFreestyle HEK293, detected with mouse anti-human FVII monoclonalantibody. Lanes are: (1) culture media; (2) FVII ELP1-90 afterpurification by phase transition; and FVII control.

FIG. 10 is an SDS-PAGE showing recombinant production of anExendin-4/ELP4-60 fusion. Lanes are: (M) Protein markers; (1) Exendin-4ELP4-60 from total lysate; (2) Exendin-4 ELP4-60 from insoluble lysate;(3) Exendin-4 ELP4-60 from soluble lysate; (4) Exendin-4 ELP4-60 from1st transition (equal volume); (5) Exendin-4 ELP4-60 from 2nd transition(concentrated); (6) Exendin-4 ELP4-60 from 3rd transition(concentrated).

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and byFactor VIIa as a comparison. As shown, FactorVIIa-ELP retains fullactivity.

FIG. 12 shows that Factor VIIa-ELP1-90 has a long PK when administeredby i.v. in rats. FactorVIIa has a T_(1/2) of about 690 min. as comparedto about 45-60 min, for Factor VIIa.

FIG. 13 shows the high in vitro activity of GLP1-ELP and Exendin-4-ELP,when compared to the activity of Exendin peptide.

FIG. 14 shows that GLP1-ELP has a T_(1/2) of about 12.9 hours whenadministered by i.v. to rats, and a T_(1/2) of about 8.6 hours whenadministered subcutaneously (SQ).

FIG. 15 shows that GLP-1 ELP has a long half-life in rabbits of about 20hours when administered i.v., and about 24 hours when administeredsub-cutaneously.

FIG. 16 shows sustained glycemic control in diabetic mice withGLP-1-ELP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic agents comprising an elasticpeptide component and a therapeutic component. The therapeutic componentmay be selected from Table 1 (e.g., selected from a Therapeutic Protein,or functional portion or functional analog thereof, listed in Table 1),or described herein. In certain embodiments, the therapeutic componentis a GLP-1 receptor agonist, such as GLP-1 or exendin-4, or may beinsulin, Factor VII/VIIa, or functional analog thereof. The elasticpeptide component exhibits a flexibility and freedom of movement thatresults from its secondary structure characteristics, and overall orsubstantial lack of a rigid tertiary structure. The elastic peptidecomponents may contain structural units related to, or derived from,sequences of the elastin protein. The elastic peptide provides certaintherapeutic advantages, such as comparatively better persistence,stability, solubility, bioavailability, half-life, and/or biologicalaction of the therapeutic component. Such properties may be determinedwith respect to, for example, an unfused or unconjugated counterpart ofthe therapeutic component. The invention further providespolynucleotides encoding the therapeutic agents of the invention, aswell as methods of treatment or prophylaxis for certain biologicalconditions, including the preferred indications listed in Table 1, andincluding diabetes (e.g., Type I and Type II), hyperglycemia, bleeding,hemophilia, and hemorrhage, among others.

For ease of reference in the ensuing discussion, set out below aredefinitions of some terms appearing in the discussion.

As used herein, the term “therapeutic agent” or “therapeutic component”refers to an agent or component capable of inducing a biological effectin vivo and/or in vitro. The biological effect may be useful fortreating and/or preventing a condition, disorder, or disease in asubject or patient.

As used herein, the term “coupled” means that the specified componentsare either directly covalently bonded to one another (e.g., via chemicalconjugation or recombinant fusion technology), or indirectly covalentlyjoined to one another (e.g., via chemical conjugation or recombinantfusion technology) through an intervening moiety or moieties, such as abridge, spacer, or linker.

As used herein, “half-life” (which generally refers to in vivo half-lifeor circulatory half-life) is the period of time that is required for a50% diminution of bioactivity of the active agent to occur. Such term isto be contrasted with “persistence,” which is the overall temporalduration of the active agent in the body, and “rate of clearance” asbeing a dynamically changing variable that may or may not be correlativewith the numerical values of half-life and persistence.

The term “functional analog” refers to a protein that is an activeanalog (e.g., either chemical or protein analog), derivative, fragment,truncation isoform or the like of a native protein. For example, thefunctional analog may be a functional analog of a therapeutic proteinlisted in Table 1, or may be a functional analog of a GLP-1 receptoragonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa. Apolypeptide is active when it retains some or all of the biologicalactivity of the corresponding native polypeptide, as determined in vivoor in one or more indicative in vitro assays. Exemplary activity assaysfor certain therapeutic proteins, which are determinative of activity,are listed Table 1. Further, such biological activities and assays forGLP-1 receptor agonists, insulin, and Factor VII/VIIa, which aredeterminative of whether a given molecule is a “functional analog,” aredescribed in detail elsewhere herein.

As used herein, the term “native,” as used in reference to an amino acidsequence, indicates that the amino acid sequence is found in anaturally-occurring protein.

As used herein, the term “spacer” refers to any moiety, peptide or otherchemical entity, that may be interposed between the elastic peptidecomponent and the therapeutic component. For example, the spacer may bea divalent group that is covalently bonded at one terminus to theelastic peptide component, and covalently bonded at the other terminusto the therapeutic component. The therapeutic agents may therefore beopen to the inclusion of additional chemical structure that does notpreclude the efficacy of the agent for its intended purpose. The spacermay, for example, be a protease-sensitive spacer moiety that is providedto control the pharmacokinetics of the agent, or the spacer may be aprotease-resistant moiety.

The therapeutic component and the elastic peptide component may becoupled with one another in any suitable covalent manner, includingchemical coupling and recombinant technology, such that the therapeuticagent is efficacious for its intended purpose, and such that thepresence of the elastic peptide component enhances the therapeuticcomponent in some functional, therapeutic or physiological aspect. Forexample, the elastic peptide-coupled therapeutic component may beenhanced in, e.g., its bioavailability, bio-unavailability,therapeutically effective dose, biological action, formulationcompatibility, resistance to proteolysis or other degradative modality,solubility, half-life or other measure of persistence in the bodysubsequent to administration, rate of clearance from the body subsequentto administration, etc. Such enhancement may be determined, for example,in relation to a corresponding unconjugated or unfused counterparttherapeutic (e.g., determined relative to native GLP-1, exendin,insulin, or Factor VII/VIIa, or a therapeutic protein described herein).

In some embodiments, the therapeutic agent of the invention circulatesor exists in the body in a soluble form, and escapes filtration by thekidney thereby persisting in the body in an active form. In someembodiments, the therapeutic agents of the invention have a molecularweight of less than the generally recognized cut-off for filtrationthrough the kidney, such as less than about 60 kD, or in someembodiments less than about 55, 50, 45, 40, 30, or 20 kDa, and persistin the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold,20-fold, or 100-fold or longer than an uncoupled (e.g., unfused orunconjugated) therapeutic counterpart.

The number of elastic peptide and/or therapeutic components permolecule, and their respective positions within the molecule, may varyamong embodiments of the invention. For example, in embodiments wherethe agent is a recombinant fusion, at least one elastic peptidecomponent may be placed at one or both of the N-terminus and theC-terminus. Where the elastic peptide component is at both theN-terminus and C-terminus of the fusion, the elastic peptide componentswill flank the therapeutic component. Alternatively, the therapeuticcomponent may be positioned at either or both of the N-terminus andC-terminus. Where the therapeutic component is at both the N-terminusand C-terminus, the therapeutic component will flank the elastic peptidecomponent. In a further embodiment, different therapeutic components arepositioned at the N-terminus and C-terminus of the molecule. Asdiscussed in detail herein, in certain embodiments, such therapeuticcomponent(s) may be released by proteolysis of a spacer moietyseparating the elastic peptide and therapeutic components. In certainembodiments, the therapeutic component may be inactive in the fusedstate, and becoming active upon proteolytic release from the elasticpeptide component(s). Alternatively, the therapeutic component remainsactive in the fused state, making proteolytic processing of thetherapeutic agent unnecessary for biological activity.

When prepared as recombinant fusions, the therapeutic agent can beprepared by known recombinant expression techniques. For example, torecombinantly produce the therapeutic agent, a nucleic acid sequenceencoding the chimeric gene is operatively linked to a suitable promotersequence such that the nucleic acid sequence encoding such fusionprotein will be transcribed and/or translated into the desired fusionprotein in the host cells. Preferred promoters are those useful forexpression in E. coli, such as the T7 promoter. Any commonly usedexpression system may be used, including eukaryotic or prokaryoticsystems. Specific examples include yeast (e.g., Saccharomyces spp.,Pichia spp.), baculovirus, mammalian, and bacterial systems, such as E.coli, and Caulobacter.

The various aspects and embodiments of the invention are described ingreater detail in the following sections.

Elastic Peptide Component

The therapeutic agent of the invention may comprise one or more elasticpeptide components. The elastic peptide components may comprise orconsist of structural peptide units or sequences that are related to, orderived from, the elastin protein (e.g., elastin-like-peptides, orELPs). Elastic peptides are useful for improving the properties oftherapeutic proteins, such as those described herein (e.g., listed inTable 1), including GLP-1 receptor agonists (e.g., GLP-1 or exendin-4),insulin, and Factor VII/VIIa in one or more of bioavailability,therapeutically effective dose, biological action, formulationcompatibility, resistance to proteolysis, solubility, half-life or othermeasure of persistence in the body subsequent to administration, and/orrate of clearance from the body.

The elastic peptide component may be constructed from structural unitsof from three to about twenty amino acids, or in some embodiments, fromfour to ten amino acids, such as five or six amino acids. The length ofthe individual structural units, may vary or may be uniform. In certainembodiments, the elastic peptide component is constructed of apolytetra-, polypenta-, polyhexa-, polyhepta-, polyocta, andpolynonapeptide motif of repeating structural units. Exemplarystructural units include units defined by SEQ ID NOS: 1-12 (below),which may be employed as repeating structural units, including tandem-repeating units, or may be employed in some combination, to create apeptide component effective for improving the properties of thetherapeutic component. Thus, the elastic peptide component may compriseor consist essentially of structural unit(s) selected from SEQ ID NOS:1-12, as defined below.

The elastic peptide component, comprising such structural units, may beof varying sizes. For example, the elastic peptide component maycomprise or consist essentially of from about 10 to about 500 structuralunits, or in certain embodiments about 15 to about 150 structural units,or in certain embodiments from about 20 to about 100 structural units,or from about 50 to about 90 structural units, including one or acombination of units defined by SEQ ID NOS: 1-12. Thus, the elasticpeptide component may have a length of from about 50 to about 2000 aminoacid residues, or from about 100 to about 600 amino acid residues, orfrom about 200 to about 500 amino acid residues, or from about 200 toabout 400 amino acid residues.

Elastic polymers (e.g., bioelastic polymers) are known and described in,for example, U.S. Pat. No. 5,520,672 to Urry et al. In general, elasticpeptides comprise elastomeric units of bioelastic pentapeptides,tetrapeptides, and/or nonapeptides (e.g., elastin-like peptides). Thus,in some embodiments the elastomeric unit is a pentapeptide, in otherembodiments the elastomeric unit is a tetrapeptide, and in still otherembodiments the elastomeric unit is a nonapeptide. Bioelastic polymersthat may be used to carry out the present invention are set forth inU.S. Pat. No. 4,474,851, which is hereby incorporated by reference inits entirety.

As disclosed in U.S. Pat. No. 4,474,851, elastomeric peptides may have asequence of regularly appearing β-turns, forming an overall spiralconformation (e.g., a β-spiral, which is a series of regularly repeatingβ-turns). The spiral structures are more open than the more commonα-helix. As a result, the atoms in the peptide backbone have a highfreedom of movement (e.g., as compared to the freedom of movement for anα-helix). This is particularly true of librational motions involvingpeptide moieties. A libration is a torsional oscillation involvingsimultaneous rotational motions of the two single bonds on each side ofa librating moiety. The moiety involved in a libration may be a singlepeptide bond or several peptide residues. For adequate freedom of motionto exist, it is important, however, that the carbonyl oxygen and theamino hydrogen of the peptide bond not be involved in hydrogen bondingto other parts of the molecule or to other molecules. Otherwise agreater energy barrier to the libration exists and motion will berestricted. Since non-hydrogen-bonded segments having freedom of motionexist in the β-spiral between the points of hydrogen bonding for theβ-turns, these segments may be said to be librationally suspended.Librationally suspended segments therefore are a structural feature thatexists in certain elastic peptides because of the repeating β-turns withrelative infrequent hydrogen bonding. Librationally suspended segmentsresulting from the β-spiral structure are thought to give rise toelasticity, as will be further discussed.

Another factor leading to the high librational freedom of such moleculesis the absence of significant polar interactions between the amino acidresidues, either intrachain or interchain, other than a hydrogen bondwithin the β-turn. The amino acid residues present are mostlyhydrophobic or glycine and accordingly do not exert significant forceson one another through space. If a significant number of charged orpolar groups were present, electrostatic interactions might limitlibrational freedom and restrict the number of available states in therelaxed (non-extended) form of the molecules. Polar and charged aminoacid residues are not strictly prohibited, however, if their presencedoes not destroy the elasticity of the elastic peptide component as awhole. For example, an occasional serine residue is present in naturallyoccurring tropoelastin without destroying elasticity. Accordingly,hydrophobic amino acid residues and glycines are preferred in formingelastomeric polypeptides of the present type although other amino acidsmay be present to a some extent.

Although not intending to be bound by theory, the elasticity ofpolypeptides of the β-turn structure may be caused by thermodynamicdrive toward greater entropy. The relaxed state of the β-spiral has alarge degree of librational freedom and thus the atoms of the peptidechain can exist in a large number of positions. When the molecules arestretched, the degree of freedom is reduced, particularly forlibrational motions, and when the tension is released, a thermodynamicdriving force toward higher entropy results in reformation of thecontracted β-spiral.

Other specific bioelastic polymers that can be used to carry out thepresent invention are described in U.S. Pat. Nos. 4,132,746, 4,187,852,4,500,700, 4,589,882, and 4,870,055, each of which are herebyincorporated by reference. Still other examples of bioelastic polymersare set forth in U.S. Pat. Nos. 6,699,294, 6,753,311, and 6,063,061,which are also incorporated by reference in their entirety.

In some embodiments, the β-turn may have the following structure, in theformation of a β-spiral:

wherein R1-R5 represent side chains of amino acid residues 1-5, and m is0 when the repeating unit is a tetrapeptide or 1 when the repeating unitis a pentapeptide. Nonapeptide repeating units generally consist ofsequential tetra- and pentapeptides. The amino acid residues may behydrophobic amino acid residues, such as those independently selectedfrom alanine, valine, leucine, isoleucine, proline, phenylalanine,tryptophan, and methionine. In many cases, the first amino acid residueof the repeating unit is a residue of valine, leucine, isoleucine orphenylalanine; the second amino acid residue is a residue of proline;the third amino acid residue is a residue of glycine; and the fourthamino acid residue is glycine or a hydrophobic residue such astryptophan, phenylalanine or tyrosine.

In some embodiments, the elastic peptide component, or in some cases thetherapeutic agent, has a size of less than about 65 kDa, or less thanabout 60 kDa, or less than about 55 kDa, or less than about 50 kDa, orless than about 40 kDa, or less than about 30 or 25 kDa. Three majorblood proteins, Human Serum Albumin (HSA), Transferrin (Tf) and IgG, orthe Fc portion of IgGs in their glycosylated form, have been exploitedto extend the half-lives of proteins and peptides for improvedtherapeutic use. These molecules are 585, 679 and 480 amino acids inlength giving molecular weights of about 66, 77, and ˜75 kDa (includingglycosylations), respectively. They are each globular and relativelycompact. The half life of these molecules is determined by a number offactors, including charge distribution, rescue of molecules by theneonatal Fc receptor (FcRn) (HSA and Fc) or cycling of Tf through the Tfreceptor (TfR), and their size which prevents filtering through thekidney glomerulus. HSA is slightly below the generally regarded cut-offfor filtration through the kidney (˜70 kDa) but its charge distributionhelps prevent this. It would be anticipated that, in order to achievehalf-life extension of the same order as that achieved with HSA, Tf andFc, a protein of at least this molecular weight range would be requiredor desirable, i.e. having over 550 amino acids and being over 65 kDa.However, an elastic peptide with a small number of amino acids relativeto HSA, Tf and Fc (e.g., in the range of about 300 to 400) and around 30to 40 kDa may have a half life that matches and/or exceeds that of HSA,Tf, and Fc.

Thus, in some embodiments, the elastic peptide component may have anextended, relatively unstructured (e.g., no definitive tertiarystructure due to rotational and/or librational freedom of the peptidebackbone) and non-globular form, and thus such molecules may have alarge expanded structure in comparison to HSA, Tf and Fc, so as toescape kidney filtration. In such embodiments, the therapeutic agents ofthe invention have a molecular weight of less than the generallyrecognized cut-off for filtration through the kidney, such as less thanabout 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30,or 25 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold,5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g.,unfused or unconjugated) therapeutic counterpart.

In certain embodiments, the elastic peptide component is an ELP thatundergoes a reversible inverse phase transition. ELP components arestructurally disordered and highly soluble in water below a transitiontemperature (Tt), but exhibit a sharp (2-3° C. range) disorder-to-orderphase transition when the temperature is raised above the Tt, leading todesolvation and aggregation of the ELP components. For example, the ELPforms insoluble polymers, when reaching sufficient size, which can bereadily removed and isolated from solution by centrifugation. Such phasetransition is reversible, and isolated insoluble ELPs can be completelyresolubilized in buffer solution when the temperature is returned belowthe Tt of the ELPs. Thus, the therapeutic agents of the invention can,in some embodiments, be separated from other contaminating proteins tohigh purity using inverse transition cycling procedures, e.g., utilizingthe temperature-dependent solubility of the therapeutic agent, or saltaddition to the medium. Successive inverse phase transition cycles canbe used to obtain a high degree of purity. In addition to temperatureand ionic strength, other environmental variables useful for modulatingthe inverse transition of the therapeutic agents include pH, theaddition of inorganic and organic solutes and solvents, side-chainionization or chemical modification, and pressure.

In certain embodiments, the ELP component does not undergo a reversibleinverse phase transition, or does not undergo such a transition at abiologically relevant Tt, and thus the improvements in the biologicaland/or physiological properties of the molecule (as described elsewhereherein), may be entirely or substantially independent of any phasetransition properties. Nevertheless, such phase transition propertiesmay impart additional practical advantages, for example, in relation tothe recovery and purification of such molecules.

In certain embodiments, the ELP component(s) may be formed of structuralunits, including but not limited to:

-   -   (a) the tetrapeptide Val-Pro-Gly-Gly, or VPGG (SEQ ID NO: 1);    -   (b) the tetrapeptide Ile-Pro-Gly-Gly, or IPGG (SEQ ID NO: 2);    -   (c) the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO: 3), or VPGXG,        where X is any natural or non-natural amino acid residue, and        where X optionally varies among polymeric or oligomeric repeats;    -   (d) the pentapeptide Ala-Val-Gly-Val-Pro, or AVGVP (SEQ ID NO:        4);    -   (e) the pentapeptide Ile-Pro-Gly-X-Gly, or IPGXG (SEQ ID NO: 5),        where X is any natural or non-natural amino acid residue, and        where X optionally varies among polymeric or oligomeric repeats;    -   (e) the pentapeptide Ile-Pro-Gly-Val-Gly, or IPGVG (SEQ ID NO:        6);    -   (f) the pentapeptide Leu-Pro-Gly-X-Gly, or LPGXG (SEQ ID NO: 7),        where X is any natural or non-natural amino acid residue, and        where X optionally varies among polymeric or oligomeric repeats;    -   (g) the pentapeptide Leu-Pro-Gly-Val-Gly, or LPGVG (SEQ ID NO:        8);    -   (h) the hexapeptide Val-Ala-Pro-Gly-Val-Gly, or VAPGVG (SEQ ID        NO: 9);    -   (I) the octapeptide Gly-Val-Gly-Val-Pro-Gly-Val-Gly, or GVGVPGVG        (SEQ ID NO: 10);    -   (J) the nonapeptide Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly, or        VPGFGVGAG (SEQ ID NO: 11); and    -   (K) the nonapeptides Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly, or        VPGVGVPGG (SEQ ID NO: 12).        Such structural units defined by SEQ ID NOS:1-12 may form        structural repeat units, or may be used in combination to form        an ELP component in accordance with the invention. In some        embodiments, the ELP component is formed entirely (or almost        entirely) of one or a combination of (e.g., 2, 3 or 4)        structural units selected from SEQ ID NOS: 1-12. In other        embodiments, at least 75%, or at least 80%, or at least 90% of        the ELP component is formed from one or a combination of        structural units selected from SEQ ID NOS: 1-12, and which may        be present as repeating units.

In certain embodiments, the ELP component(s) contain repeat units,including tandem repeating units, of the pentapeptide Val-Pro-Gly-X-Gly(SEQ ID NO:3), where X is as defined above, and where the percentage ofVal-Pro-Gly-X-Gly (SEQ ID NO:3) pentapeptide units taken with respect tothe entire ELP component (which may comprise structural units other thanVPGXG (SEQ ID NO:3)) is greater than about 75%, or greater than about85%, or greater than about 95% of the ELP component. The ELP componentmay contain motifs having a 5 to 15-unit repeat (e.g. about 10-unitrepeat) of the pentapeptide of SEQ ID NO: 3, with the guest residue Xvarying among at least 2 or at least 3 of the units. The guest residuesmay be independently selected, such as from the amino acids V, I, L, A,G, and W (and may be selected so as to retain a desired inverse phasetransition property). The repeat motif itself may be repeated, forexample, from about 5 to about 12 times, such as about 8 to 10 times, tocreate an exemplary ELP component. The ELP component as described inthis paragraph may of course be constructed from any one of thestructural units defined by SEQ ID NOS: 1-12, or a combination thereof.

In some embodiments, the ELP component may include a β-turn structure.Exemplary peptide sequences suitable for creating a β-turn structure aredescribed in International Patent Application PCT/US96/05186, which ishereby incorporated by reference in its entirety. For example, thefourth residue (X) in the elastin pentapeptide sequence, VPGXG (SEQ IDNO:3), can be altered without eliminating the formation of a β-turn.Alternatively, the ELP component may lack a β-turn, or otherwise have adifferent conformation and/or folding character.

In certain embodiments, the ELP components include polymeric oroligomeric repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where theguest residue X is any amino acid. X may be a naturally occurring ornon-naturally occurring amino acid. In some embodiments, X is selectedfrom alanine, arginine, asparagine, aspartic acid, cysteine, glutamicacid, glutamine, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, serine, threonine, tryptophan, tyrosine andvaline. In some embodiments, X is a natural amino acid other thanproline or cysteine.

The guest residue X (e.g., with respect to SEQ ID NO: 3, or other ELPstructural unit) may be a non-classical (non-genetically encoded) aminoacid. Examples of non-classical amino acids include: D-isomers of thecommon amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid,A-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu, ε-Ahx, 6-aminohexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid,ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline,homocitrulline, cysteic acid, t-butylglycine, t-butylalanine,phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids,designer amino acids such as β-methyl amino acids, Cα-methyl aminoacids, Nα-methyl amino acids, and amino acid analogs in general.

Selection of X is independent in each ELP structural unit (e.g., foreach structural unit defined herein having a guest residue X). Forexample, X may be independently selected for each structural unit as anamino acid having a positively charged side chain, an amino acid havinga negatively charged side chain, or an amino acid having a neutral sidechain, including in some embodiments, a hydrophobic side chain.

In still other embodiments, the ELP component(s) may include polymericor oligomeric repeats of the pentapeptides VPGXG (SEQ ID NO:3), IPGXG(SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination thereof, where Xis as defined above.

In each embodiment, the structural units, or in some cases polymeric oroligomeric repeats, of the elastic peptide sequences may be separated byone or more amino acid residues that do not eliminate the overall effectof the molecule, that is, in imparting certain improvements to thetherapeutic component as described. In certain embodiments, such one ormore amino acids also do not eliminate or substantially affect the phasetransition properties where ELP components are employed (relative to thedeletion of such one or more amino acids).

For ELP sequences, in each repeat, X is independently selected. Thestructure of the resulting ELP components may be described using thenotation ELPk [X_(i)Y_(j)-n], where k designates a particular ELP repeatunit, the bracketed capital letters are single letter amino acid codesand their corresponding subscripts designate the relative ratio of eachguest residue X in the structural units (where applicable), and ndescribes the total length of the ELP in number of the structuralrepeats. For example, ELP1 [V₅A₂G₃-10]designates an ELP componentcontaining 10 repeating units of the pentapeptide VPGXG (SEQ ID NO:3),where X is valine, alanine, and glycine at a relative ratio of 5:2:3;ELP1 [K₁V₂F₁-4] designates an ELP component containing 4 repeating unitsof the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, andphenylalanine at a relative ratio of 1:2:1; ELP1 [K₁V₇F₁-9] designates apolypeptide containing 9 repeating units of the pentapeptide VPGXG (SEQID NO:3), where X is lysine, valine, and phenylalanine at a relativeratio of 1:7:1; ELP1 [V-5] designates a polypeptide containing 5repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X isexclusively valine; ELP1 [V-20] designates a polypeptide containing 20repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X isexclusively valine; ELP2 [5] designates a polypeptide containing 5repeating units of the pentapeptide AVGVP (SEQ ID NO:4); ELP3 [V-5]designates a polypeptide containing 5 repeating units of thepentapeptide IPGXG (SEQ ID NO:5), where X is exclusively valine; ELP4[V-5] designates a polypeptide containing 5 repeating units of thepentapeptide LPGXG (SEQ ID NO:7), where X is exclusively valine. SuchELP components as described in this paragraph may be used in connectionwith the present invention to increase the therapeutic properties of thetherapeutic component.

Further, the Tt is a function of the hydrophobicity of the guestresidue. Thus, by varying the identity of the guest residue(s) and theirmole fraction(s), ELPs can be synthesized that exhibit an inversetransition over a 0-100° C. range. Thus, the Tt at a given ELP lengthmay be decreased by incorporating a larger fraction of hydrophobic guestresidues in the ELP sequence. Examples of suitable hydrophobic guestresidues include valine, leucine, isoleucine, phenyalanine, tryptophanand methionine. Tyrosine, which is moderately hydrophobic, may also beused. Conversely, the Tt may be increased by incorporating residues,such as those selected from the group consisting of: glutamic acid,cysteine, lysine, aspartate, alanine, asparagine, serine, threonine,glycine, arginine, and glutamine; preferably selected from alanine,serine, threonine and glutamic acid.

The ELP component in some embodiments is selected or designed to providea Tt ranging from about 10 to about 80° C., such as from about 35 toabout 60° C., or from about 38 to about 45° C. In some embodiments, theTt is greater than about 40° C. or greater than about 42° C., or greaterthan about 45° C., or greater than about 50° C. The transitiontemperature, in some embodiments, is above the body temperature of thesubject or patient (e.g., >37° C.) thereby remaining soluble in vivo, orin other embodiments, the Tt is below the body temperature (e.g., <37°C.) to provide alternative advantages, such as in vivo formation of adrug depot for sustained release of the therapeutic agent.

The Tt of the ELP component can be modified by varying ELP chain length,as the Tt generally increases with decreasing MW. For polypeptideshaving a molecular weight >100,000, the hydrophobicity scale developedby Urry et al. (PCT/US96/05186, which is hereby incorporated byreference in its entirety) is preferred for predicting the approximateTt of a specific ELP sequence. However, in some embodiments, ELPcomponent length can be kept relatively small, while maintaining atarget Tt, by incorporating a larger fraction of hydrophobic guestresidues (e.g., amino acid residues having hydrophobic side chains) inthe ELP sequence. For polypeptides having a molecular weight <100,000,the Tt may be predicted or determined by the following quadraticfunction: Tt=M₀+M₁X+M₂X² where X is the MW of the fusion protein, andM₀=116.21; M₁=−1.7499; M₂=0.010349.

While the Tt of the ELP component, and therefore of the ELP componentcoupled to a therapeutic component, is affected by the identity andhydrophobicity of the guest residue, X, additional properties of themolecule may also be affected. Such properties include, but are notlimited to solubility, bioavailability, persistence, and half -life ofthe molecule.

As described in PCT/US2007/077767 (published as WO 2008/030968), whichis hereby incorporated by reference in its entirety, the ELP-coupledtherapeutic component can retain the therapeutic component's biologicalactivity. Additionally, ELPs themselves can exhibit long half-lives.Therefore, ELP components in accordance with the present inventionsubstantially increase (e.g. by greater than 10%, 20%, 30%, 50%, 100%,200%, 500% or more, in specific embodiments) the half-life of thetherapeutic component when conjugated thereto. Such half-life (or insome embodiments persistance or rate of clearance) is determined incomparison to the half-life of the free (unconjugated or unfused) formof the therapeutic component. Furthermore, ELPs may target high bloodcontent organs, when administered in vivo, and thus, can partition inthe body, to provide a predetermined desired corporeal distributionamong various organs or regions of the body, or a desired selectivity ortargeting of a therapeutic agent. In sum, the therapeutic agentscontemplated by the invention are administered or generated in vivo asactive compositions having extended half-lives (e.g., circulatoryhalf-life), among other potential benefits described herein.

The invention thus provides various agents for therapeutic (in vivo)application, where the therapeutic component is biologically active.Such therapeutic components include, without limitation, growth hormone(GH) particularly human and bovine growth hormone, growthhormone-releasing hormones; interferon including α-, β-, orγ-interferons, etc, interleukin-I; interleukin-II; erythropoietinincluding α- and β-erythropoietin (EPO), granulocyte colony stimulatingfactor (GCSF), granulocyte macrophage colony stimulating factor(GM-CSF), anti-agiogenic proteins (e.g., angiostatin, endostatin) PACAPpolypeptide (pituitary adenylate cyclase activating polypeptide),vasoactive intestinal peptide (VIP), thyrotrophin releasing hormone(TRH), corticotropin releasing hormone (CRH), vasopressin, argininevasopressin (AVP), angiotensin, calcitonin, atrial naturetic factor,somatostatin, adrenocorticotropin, gonadotropin releasing hormone,oxytocin, insulin, somatotropin, plasminogen tissue activator,coagulation factors including coagulation factors VIII and IX,glucosylceramidase, sargramostim, lenograstin, filgrastin, dornase-α,molgramostim, PEG-L-asparaginase, PEG-adenosine deaminase, hirudin,eptacog-α(human blood coagulation factor VIIa) nerve growth factors,transforming growth factor, epidermal growth factor, basic fibroblastgrowth factor, VEGF; heparin including low molecular weight heparin,calcitonin; antigens; monoclonal antibodies; vancomycin; desferrioxamine(DFO); parathyroid hormone, an immunogen or antigen, an antibody such asa monoclonal antibody.

Where the therapeutic component is an antibody or antibody sequence, theantibody may be of any isotype, including IgG, IgM, IgA, IgD, and IgE.Where the antibody is IgG, the subtype may be IgGi, IgG2, IgG3, or IgG4.The antibody sequence may be humanized or chimeric. The term “antibody”as used herein includes antibody fragments or segments that retain thecapability of binding to a target antigen, for example, Fab, F(ab′)2,and Fv fragments, and the corresponding fragments obtained fromantibodies other than IgG. Examples of therapeutic antibodies includebut are not limited to herceptin, rituxan, campath, gemtuzumab,herceptin, panorex, rituximab, bexxar, edrecolomab, alemtuzumab,mylotrag, IMC-C225, smartin 195, and mitomomab.

The therapeutic component may also be a therapeutic component listed inTable 1 (e.g., full length or functional portions or functional analogsthereof), as well as GLP-1 receptor agonists such as GLP-1 or exendin-4,insulin, or Factor VII/VIIa, and functional analogs thereof. Thestructure and activity of such therapeutic components are described indetail below. In some forms of the therapeutic agent, the coupling ofthe therapeutic component to the elastic peptide is effected by directcovalent bonding or indirect (through appropriate spacer groups) bonding(as described elsewhere herein). Further, the therapeutic component(s)and the elastic peptide component(s) can be structurally arranged in anysuitable manner involving such direct or indirect covalent bonding,relative to one another.

Glucagon-Like Peptide (GLP)-1 Receptor Agonists

In certain embodiments of the invention, the therapeutic agent comprisesan ELP component fused or conjugated to a GLP-1 receptor agonist, suchas GLP-1, exendin-4, or functional analogs thereof.

Human GLP-1 is a 37 amino acid residue peptide originating frompreproglucagon which is synthesized in the L-cells in the distal ileum,in the pancreas, and in the brain. Processing of preproglucagon to giveGLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells.A simple system is used to describe fragments and analogs of thispeptide. For example, Gly⁸-GLP-1 (7-37) designates a fragment of GLP-1formally derived from GLP-1 by deleting the amino acid residues Nos. 1to 6 and substituting the naturally occurring amino acid residue inposition 8 (Ala) by Gly. Similarly, Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-37) designates GLP-1 (7-37) wherein theε-amino group of the Lys residue in position 34 has beentetradecanoylated. Where reference in this text is made to C-terminallyextended GLP-1 analogues, the amino acid residue in position 38 is Argunless otherwise indicated, the optional amino acid residue in position39 is also Arg unless otherwise indicated and the optional amino acidresidue in position 40 is Asp unless otherwise indicated. Also, if aC-terminally extended analogue extends to position 41, 42, 43, 44 or 45,the amino acid sequence of this extension is as in the correspondingsequence in human preproglucagon unless otherwise indicated.

The parent peptide of GLP-1, proglucagon (PG), has several cleavagesites that produce various peptide products dependent on the tissue oforigin including glucagon (PG[32-62]) and GLP-1[7-36]NH₂ (PG[72-107]) inthe pancreas, and GLP-1[7-37] (PG[78-108 ]) and GLP-1[7-36]NH₂ (PG[78-107]) in the L cells of the intestine where GLP-1[7-36]NH₂ (78-107PG) is the major product. The GLP-1 component in accordance with theinvention may be any biologically active product or derivative ofproglocagon, or functional analog thereof, including: GLP-1 (1-35),GLP-1(1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1(1-39), GLP-1 (1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1(7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) andGLP-1 (7-41), or a analog of the foregoing. Generally, the GLP-1component in some embodiments may be expressed as GLP-1 (A-B), where Ais an integer from 1 to 7 and B is an integer from 38 to 45, optionallywith one or more amino acid substitutions as defined below.

As an overview, after processing in the intestinal L-cells, GLP-1 isreleased into the circulation, most notably in response to a meal. Theplasma concentration of GLP-1 rises from a fasting level ofapproximately 15 pmol/L to a peak postprandial level of 40 pmol/L. For agiven rise in plasma glucose concentration, the increase in plasmainsulin is approximately threefold greater when glucose is administeredorally compared with intravenously (Kreymann et al., 1987, Lancet2(8571): 1300-4). This alimentary enhancement of insulin release, knownas the incretin effect, is primarily humoral and GLP-1 is now thought tobe the most potent physiological incretin in humans. GLP-1 mediatesinsulin production via binding to the GLP-1 receptor, known to beexpressed in pancreatic β cells. In addition to the insulinotropiceffect, GLP-1 suppresses glucagon secretion, delays gastric emptying(Wettergen et al., 1993, Dig Dis Sci 38: 665-73) and may enhanceperipheral glucose disposal (D'Alessio et al., 1994, J. Clin Invest 93:2293-6).

A combination of actions gives GLP-1 unique therapeutic advantages overother agents currently used to treat non-insulin-dependent diabetesmellitus (NIDDM). First, a single subcutaneous dose of GLP-1 cancompletely normalize post prandial glucose levels in patients with NIDDM(Gutniak et al., 1994, Diabetes Care 17: 1039-44). This effect may bemediated both by increased insulin release and by a reduction inglucagon secretion. Second, intravenous infusion of GLP-1 can delaypostprandial gastric emptying in patients with NIDDM (Williams et al.,1996, J. Clin Endo Metab 81: 327-32). Third, unlike sulphonylureas, theinsulinotropic action of GLP-1 is dependent on plasma glucoseconcentration (Holz et al., 1993, Nature 361:362-5). Thus, the loss ofGLP-1-mediated insulin release at low plasma glucose concentrationprotects against severe hypoglycemia.

When given to healthy subjects, GLP-1 potently influences glycemiclevels as well as insulin and glucagon concentrations (Orskov, 1992,Diabetologia 35:701-11), effects which are glucose dependent (Weir etal., 1989, Diabetes 38: 338-342). Moreover, it is also effective inpatients with diabetes (Gutniak, M., 1992, N. Engl J Med 226: 1316-22),normalizing blood glucose levels in type 2 diabetic subjects andimproving glycemic control in type 1 patients (Nauck et al., 1993,Diabetologia 36: 741-4, Creutzfeldt et al., 1996, Diabetes Care19:580-6).

GLP-1 is, however, metabolically unstable, having a plasma half-life(T_(1/2)) of only 1-2 minutes in vivo. Moreover, exogenouslyadministered GLP-1 is also rapidly degraded (Deacon et al., 1995,Diabetes 44: 1126-31). This metabolic instability has limited thetherapeutic potential of native GLP-1.

GLP-1[7-36]NH₂ has the following amino acid sequence:HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be employed asthe GLP-1 component in accordance with the invention. Alternatively, theGLP-1 component may contain glycine (G) at the second position, giving,for example, the sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO:17). The GLP-1 component may be a biologically active fragment of GLP-1,for example, as disclosed in US 2007/0041951, which is herebyincorporated by reference in its entirety. Other fragments and modifiedsequences of GLP-1 are known in the art (U.S. Pat. Nos. 5,614,492;5,545,618; European Patent Application, Publication No. EP 0658568 A1;WO 93/25579, which are hereby incorporated by reference in theirentireties). Such fragments and modified sequences may be used inconnection with the present invention, as well as those described below.

Certain structural and functional analogs of GLP-1 have been isolatedfrom the venom of the Gila monster lizards (Heloderma suspectum andHeloderma horridum) and have shown clinical utility. Such molecules finduse in accordance with the present invention. In particular, exendin-4is a 39 amino acid residue peptide isolated from the venom of Helodermasuspectum and shares approximately 52% homology with human GLP-1.Exendin-4 is a potent GLP-1 receptor agonist that stimulates insulinrelease, thereby lowering blood glucose levels. Exendin-4 has thefollowing amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS(SEQ ID NO: 14). A synthetic version of exendin-4 known as exenatide(marketed as Byetta®) has been approved for the treatment of Type-2Diabetes. Although exenatide is structurally analogous to native GLP-1,it has a longer half-life after injection.

While exenatide has the ability to lower blood glucose levels on itsown, it can also be combined with other medications such as metformin, athiozolidinedione, a sulfonylureas, and/or insulin to improve glucosecontrol. Exenatide is administered by injection subcutaneously twice perday using a pre-filled pen device. Typical human responses to exenatideinclude improvements in the initial rapid release of endogenous insulin,an increase in β-cell growth and replication, suppression of pancreaticglucagon release, delayed gastric emptying, and reduced appetite—all ofwhich function to lower blood glucose. Unlike sulfonylureas andmeglitinides, exenatide increases insulin synthesis and secretion in thepresence of glucose only, thus lessening the risk of hypoglycemia.Despite the therapeutic utility of exenatide, it has certain undesirabletraits, including the requirement of twice daily injections,gastrointestional side effects, and similar to native GLP-1, arelatively short half-life (i.e. approximately 2 hr).

Various functional analogs of GLP-1 and exendin-4 are known, and whichfind use in accordance with the invention. These include liraglutide(Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche, WO00/034331),CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010 (Zealand Pharma,Sanofi-Aventis, WO01/004156), and LY548806 (Eli Lilly, WO03/018516).

Liraglutide, also known as NN2211, is a GLP-1 receptor agonist analogthat has been designed for once-daily injection (Harder et al., 2004,Diabetes Care 27: 1915-21). Liraglutide has been tested in patients withtype-2 diabetes in a number of studies and has been shown to beeffective over a variety of durations. In one study, treatment withliraglutide improved glycemic control, improved (β-cell function, andreduced endogenous glucose release in patients with type-2 diabetesafter one week of treatment (Degn et al., 2004, Diabetes 53: 1187-94).In a similar study, eight weeks of 0.6-mg liraglutide therapysignificantly improved glycemic control without increasing weight insubjects with type 2 diabetes compared with those on placebo (Harder etal., 2004, Diabetes Care 27: 1915-21).

Thus, in certain embodiments, the GLP-1 receptor agonist in accordancewith the invention is as described in WO98/008871, which is herebyincorporated by reference in its entirety. The GLP-1 receptor agonistmay have at least one lipophilic substituent, in addition to one, two,or more amino acid substitutions with respect to native GLP-1. Forexample, the lipophilic substituent may be an acyl group selected fromCH₃(CH₂)_(n)CO—, wherein n is an integer from 4 to 38, such as aninteger from 4 to 24. The lipophilic substituent may be an acyl group ofa straight-chain or branched alkyl or fatty acid (for example, asdescribed in WO98/008871, which description is hereby incorporated byreference).

In certain embodiments, the GLP-1 component is Arg²⁶-GLP-1 (7-37),Arg³⁴-GLP-1(7-37), Lys³⁶-GLP-1 (7-37), Arg^(26,34)Lys³⁶-GLP-I (7-37),Arg^(26,34)Lys³⁸-GLP-I (7-38), Arg^(28,34) Lys³⁹-GLP-1 (7-39),Arg^(26,34)Lys⁴⁰-GLP-1(7-40), Arg²⁶Lys³⁶-GLP-1(7-37),Arg³⁴Lys³⁶-GLP-1(7-37), Arg²⁶Lys³⁹-GLP-1(7-39), Arg³⁴Lys⁴⁰-GLP-1(7-40),Arg^(26,34)Lys^(36,39)-GLP-I (7-39), Arg^(26,34)Lys^(36,40)-GLP-1(7-40),Gly⁸Arg²⁶-GLP-1(7-37); Gly⁸Arg³⁴-GLP-1(7-37); Gly⁸Lys³⁸-GLP-1(7-37);Gly⁸Arg^(26,34)Lys³⁶-GLP-1 (7-37), Gly⁸Arg^(26,34)Lys³⁹-GLP-1 (7-39),Gly⁸Arg^(26,34)Lys⁴⁰-GLP-1 (7-40), Gly⁸Arg²⁶Lys³⁶-GLP-1 (7-37),Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37), Gly⁸Arg²⁶Lys³⁹- GLP-1(7-39);Gly⁸Arg³⁴Lys⁴⁰-GLP-1(7-40), Gly⁸Arg^(28,34)Lys^(36,39)-GLP-1(7-39) andGly⁸Arg^(26,34)Lys^(35,40)-GLP-1(7-40), each optionally having alipophilic substituent. For example, the GLP-1 receptor agonist may havethe sequence/structureArg³⁴Lys²⁶-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-I(7-37).

Taspoglutide, also known as R1583 or BIM 51077, is a GLP-1 receptoragonist that has been shown to improve glycemic control and lower bodyweight in subjects with type 2 diabetes mellitus treated with metformin(Abstract No. A-1604, Jun. 7, 2008, 68th American Diabetes AssociationMeeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as describedin WO00/034331, which is hereby incorporated by reference in itsentirety. In certain exemplary embodiments, the GLP-1 receptor agonisthas the sequence [Aib^(8,35)]hGLP-1(7-36)NH₂ (e.g. taspoglutide),wherein Aib is alpha-aminoisobutyric acid.

CJC-1131 is a GLP-1 analog that consists of a DPP-IV-resistant form ofGLP-1 joined to a reactive chemical linker group that allows GLP-1 toform a covalent and irreversible bond with serum albumin followingsubcutaneous injection (Kim et al., 2003, Diabetes 52: 751-9). In a12-week, randomized, double-blind, placebo-controlled multicenter study,CJC-1131 and metformin treatment was effective in reducing fasting bloodglucose levels in type 2 diabetes patients (Ratner et al., Abstract No.10-OR, Jun. 10-14th, 2005, 65th American Diabetes Association Meeting,San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as describedin WO00/069911, which is hereby incorporated by reference in itsentirety. In some embodiments, the GLP-1 receptor agonist is modifiedwith a reactive group which reacts with amino groups, hydroxyl groups orthiol groups on blood components to form a stable covalent bond. Incertain embodiments, the GLP-1 receptor agonist is modified with areactive group selected from the group consisting of succinimidyl andmaleimido groups. In certain exemplary embodiments, the GLP-1 receptoragonist has the sequence/structure: D-Ala⁸Lys³⁷-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetamide))-GLP-1(7-37) (e.g. CJC-1131).

AVE0010, also known as ZP-10, is a GLP-1 receptor agonist that may beemployed in connection with the invention. In a recent double-blindstudy, patients treated with once daily dosing of AVE0010 demonstratedsignificant reductions in HbA1c levels (Ratner et al., Abstract No.433-P, 68th American Diabetes Association Meeting, San Francisco,Calif.). At the conclusion of the study, the percentages of patientswith HbA1c <7% ranged from 47-69% for once daily dosing compared to 32%for placebo. In addition, AVE0010 treated patients showed dose-dependentreductions in weight and post-prandial plasma glucose.

Thus, in certain embodiments, the GLP-1 receptor agonist is as describedin WO01/004156, which is hereby incorporated by reference in itsentirety. For example, the GLP-1 receptor agonist may have the sequence:

(SEQ ID NO: 18) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2(e.g. AVE0010).

LY548806 is a GLP-1 derivative designed to be resistant to proteolysisby dipeptidase-peptidyl IV (DPP-IV) (Jackson et al., Abstract No. 562,Jun. 10-14, 2005, 65th American Diabetes Association Meeting, SanFrancisco, Calif.). In an animal model of hyperglycemia, LY548806 hasbeen shown to produce a significant lowering of blood glucose levelsduring the hyperglycemic phase (Saha et al., 2006, J. Pharm. Exp. Ther.316: 1159-64). Moreover, LY548806 was shown to produce a significantincrease in insulin levels consistent with its known mechanism ofaction, namely stimulation of insulin release in the presence ofhyperglycemia.

Thus, in certain embodiments, the GLP-1 receptor agonist is as describedin WO03/018516, which is hereby incorporated by reference in itsentirety. In some embodiments, the therapeutic agents of the presentinvention comprise GLP-1 analogs wherein the backbone for such analogsor fragments contains an amino acid other than alanine at position 8(position 8 analogs). The backbone may also include L -histidine,D-histidine, or modified forms of histidine such as desamino-histidine,2-amino-histidine, (β-hydroxy-histidine, homohistidine,α-fluoromethyl-histidine, or α-methyl-histidine at position 7. In someembodiments, these position 8 analogs may contain one or more additionalchanges at positions 12, 16, 18, 19, 20, 22, 25, 27, 30, 33, and 37compared to the corresponding amino acid of native GLP-1. In otherembodiments, these position 8 analogs may contain one or more additionalchanges at positions 16, 18, 22, 25 and 33 compared to the correspondingamino acid of native GLP-1. In certain exemplary embodiments, the GLP-1receptor agonist has the sequence: HVEGTFTSDVSSYLEEQAAKEFIAWLIKGRG-OH(SEQ ID NO: 19) (e.g. LY548806).

Thus, the present invention provides therapeutic agents comprising anelastic peptide (e.g., an ELP) and a GLP-1 receptor agonist. Forexample, in certain embodiments, the GLP-1 receptor agonist is GLP-1(SEQ ID NO:13, 17, or 59) or a functional analog thereof. In otherembodiments, the GLP-1 receptor agonist is exendin-4 (SEQ ID NO:14) or afunctional analog thereof. Such functional analogs of GLP-1 or exendin-4include functional fragments truncated at the C-terminus by from 1 to 10amino acids, including by 1, 2, 3, or up to about 5 amino acids (withrespect to SEQ ID NOS: 13, 14, 17, or 59). Such functional analogs maycontain from 1 to 10 amino acid insertions, deletions, and/orsubstitutions (collectively) with respect to the native sequence (e.g.,SEQ ID NOS 13, 14, and 59), and in each case retaining the activity ofthe peptide. For example, the functional analog of GLP-1 or exendin-4may have from 1 to about 3, 4, or 5 insertions, deletions and/orsubstitutions (collectively) with respect to SEQ ID NOS: 13, 59 and 14,and in each case retaining the activity of the peptide. Such activitymay be confirmed or assayed using any available assay, including thosedescribed herein. In these or other embodiments, the GLP-1 receptoragonist component has at least about 50%, 75%, 80%, 85%, 90%, or 95%identity with the native sequence (SEQ ID NOS: 13, 59, and 14). Thedetermination of sequence identity between two sequences (e.g., betweena native sequence and a functional analog) can be accomplished using anyalignment tool, including Tatusova et al., Blast 2 sequences—a new toolfor comparing protein and nucleotide sequences, FEMS Microbiol Lett.174:247-250 (1999). Such functional analogs may further compriseadditional chemical modifications, such as those described in thissection and/or others known in the art.

In certain embodiments, the GLP1-ELP fusion has a sequence exemplifiedherein as SEQ ID NOS: 54 and 56. When processed, the mature form of suchfusion protein will begin with the His⁷ of GLP.

In another aspect, the present invention provides methods for thetreatment or prevention of type 2 diabetes, impaired glucose tolerance,type 1 diabetes, hyperglycemia, obesity, binge eating, bulimia,hypertension, syndrome X, dyslipidemia, cognitive disorders,atheroschlerosis, non-fatty liver disease, myocardial infarction,coronary heart disease and other cardiovascular disorders. The methodcomprises administering the therapeutic agent comprising theelastin-like peptide (ELP) and the GLP-1 receptor agonist (as describedabove) to a patient in need of such treatment. In these or otherembodiments, the present invention provides methods for decreasing foodintake, decreasing β-cell apoptosis, increasing β-cell function andβ-cell mass, and/or for restoring glucose sensitivity to β-cells.Generally, the patient may be a human or non-human animal patient (e.g.,dog, cat, cow, or horse). Peferably, the patient is human.

The treatment with a ELP/GLP-1 receptor agonist compound according tothe present invention may also be combined with one or morepharmacologically active substances, e.g. selected from antidiabeticagents, antiobesity agents, appetite regulating agents, antihypertensiveagents, agents for the treatment and/or prevention of complicationsresulting from or associated with diabetes and agents for the treatmentand/or prevention of complications and disorders resulting from orassociated with obesity. In the present context, the expression“antidiabetic agent” includes compounds for the treatment and/orprophylaxis of insulin resistance and diseases wherein insulinresistance is the pathophysiological mechanism.

The ability of a GLP-1 or exendin-4 analog, or an GLP-1 receptoragonist/elastic peptide compound, to bind the GLP-1 receptor may bedetermined by standard methods, for example, by receptor-bindingactivity screening procedures which involve providing appropriate cellsthat express the GLP-1 receptor on their surface, for example,insulinoma cell lines such as RINmSF cells or INS-1 cells. In additionto measuring specific binding of tracer to membrane usingradioimmunoassay methods, cAMP activity or glucose dependent insulinproduction can also be measured. In one method, a polynucleotideencoding the GLP-1 receptor is employed to transfect cells to therebyexpress the GLP-1 receptor protein. Thus, these methods may be employedfor testing or confirming whether a suspected GLP-1 receptor agonist isactive. An exemplary assay is described in greater detail herein.

In addition, known methods can be used to measure or predict the levelof biologically activity of a GLP-1 receptor agonist or GLP-1 receptoragonist/elastic peptide in vivo (See e.g. Siegel, et al., 1999, RegulPept 79(2-3): 93-102). In particular, GLP-1 receptor agonists or GLP-1receptor agonist/elastic peptide compounds can be assessed for theirability to induce the production of insulin in vivo using a variety ofknown assays for measuring GLP-1 activity. For example, a GLP-1 receptoragonist/elastic peptide compound can be introduced into a cell, such asan immortalized β-cell, and the resulting cell can be contacted withglucose. If the cell produces insulin in response to the glucose, thenthe modified GLP-1 is generally considered biologically active in vivo(Fehmann et al., 1992, Endocrinology 130: 159-166). An exemplary assayis described in greater detail herein.

The ability of an GLP-1 receptor agonist/elastic peptide compound toenhance β-cell proliferation, inhibit (β-cell apoptosis, and regulateislet growth may also be measured using known assays. Pancreatic β-cellproliferation may be assessed by ³H -tymidine or BrdU incorporationassays (See e.g. Buteau et al., 2003, Diabetes 52: 124-32), whereinpancreatic β-cells such as INS(832/13) cells are contacted with a GLP-1receptor agonist/elastic peptide compound and analyzed for increases in³H-thymidine or BrdU incorporation. The antiapoptotic activity of aGLP-1 receptor agonist/elastic peptide compound can be measured incultured insulin-secreting cells and/or in animal models where diabetesoccurs as a consequence of an excessive rate of beta-cell apoptosis (Seee.g. Bulotta et al., 2004, Cell Biochem Biophys 40(3 suppl): 65-78).

In addition to GLP-1, other peptides of this family, such as thosederived from processing of the pro-glucagon gene, such as GLP-2, GIP,and oxyntomodulin, could be conjugated or fused to the elastic peptidecomponent (as described herein) to enhance the therapeutic potential.

Insulin

In other embodiments, the present invention provides a therapeutic agentcomprising an elastin peptide component coupled to insulin (e.g., viafusion or conjugation). Insulin injections, e.g. of human insulin, canbe used to treat diabetes. The insulin-making cells of the body arecalled β-cells, and they are found in the pancreas gland. These cellsclump together to form the “islets of Langerhans”, named for the Germanmedical student who described them.

The synthesis of insulin begins at the translation of the insulin gene,which resides on chromosome 11. During translation, two introns arespliced out of the mRNA product, which encodes a protein of 110 aminoacids in length. This primary translation product is calledpreproinsulin and is inactive. It contains a signal peptide of 24 aminoacids in length, which is required for the protein to cross the cellmembrane.

Once the preproinsulin reaches the endoplasmic reticulum, a proteasecleaves off the signal peptide to create proinsulin. Proinsulin consistsof three domains: an amino-terminal B chain, a carboxyl-terminal Achain, and a connecting peptide in the middle known as the C-peptide.Insulin is composed of two chains of amino acids named chain A (21 aminoacids—GIVEQCCASVCSLYQLENYCN) (SEQ ID NO: 15) and chain B (30 amino acidsFVNQHLCGSHLVEALYLVCGERGFFYTPKA) (SEQ ID NO: 16) that are linked togetherby two disulfide bridges. There is a 3rd disulfide bridge within the Achain that links the 6th and 11th residues of the A chain together. Inmost species, the length and amino acid compositions of chains A and Bare similar, and the positions of the three disulfide bonds are highlyconserved. For this reason, pig insulin can replace deficient humaninsulin levels in diabetes patients. Today, porcine insulin has largelybeen replaced by the mass production of human proinsulin by bacteria(recombinant insulin).

Insulin molecules have a tendency to form dimers in solution, and in thepresence of zinc ions, insulin dimers associate into hexamers. Whereasmonomers of insulin readily diffuse through the blood and have a rapideffect, hexamers diffuse slowly and have a delayed onset of action. Inthe design of recombinant insulin, the structure of insulin can bemodified in a way that reduces the tendency of the insulin molecule toform dimers and hexamers but that does not interrupt binding to theinsulin receptor. In this way, a range of preparations are made, varyingfrom short acting to long acting.

Within the endoplasmic reticulum, proinsulin is exposed to severalspecific peptidases that remove the C-peptide and generate the matureand active form of insulin. In the Golgi apparatus, insulin and freeC-peptide are packaged into secretory granules, which accumulate in thecytoplasm of the β-cells. Exocytosis of the granules is triggered by theentry of glucose into the beta cells. The secretion of insulin has abroad impact on metabolism.

There are two phases of insulin release in response to a rise inglucose. The first is an immediate release of insulin. This isattributable to the release of preformed insulin, which is stored insecretory granules. After a short delay, there is a second, moreprolonged release of newly synthesized insulin.

Once released, insulin is active for a only a brief time before it isdegraded by enzymes. Insulinase found in the liver and kidneys breaksdown insulin circulating in the plasma, and as a result, insulin has ahalf-life of only about 6 minutes. This short duration of action resultsin rapid changes in the circulating levels of insulin.

Insulin analogs have been developed with improved therapeutic properties(Owens et al., 2001, Lancet 358: 739-46; Vajo et al., 2001, Endocr Rev22: 706-17), and such analogs may be employed in connection with thepresent invention. Various strategies, including elongation of theCOOH-terminal end of the insulin B-chain and engineering of fattyacid-acylated insulins with substantial affinity for albumin are used togenerate longer-acting insulin analogs. However, in vivo treatments withavailable longer-acting insulin compounds still result in a highfrequency of hypo- and hyperglycemic excursions and modest reduction inHbA_(1c). Accordingly, development of a truly long-acting and stablehuman insulin analog still remains an important task.

Functional analogs of insulin that may be employed in accordance withthe invention include rapid acting analogs such as lispro, aspart andglulisine, which are absorbed rapidly (<30 minutes) after subcutaneousinjection, peak at one hour, and have a relatively short duration ofaction (3 to 4 hours). In addition, two long acting insulin analogs havebeen developed: glargine and detemir, and which may be employed inconnection with the invention. The long acting insulin analogs have anonset of action of approximately two hours and reach a plateau ofbiological action at 4 to 6 hours, and may last up to 24 hours.

Thus, in one embodiment, the insulin component may contain the A and/orB chain of lispro (also known as Humalog, Eli Lilly). Insulin lisprodiffers from human insulin by the substitution of proline with lysine atposition 28 and the substitution of lysine with proline at position 29of the insulin B chain. Although these modifications do not alterreceptor binding, they help to block the formation of insulin dimers andhexamers, allowing for larger amounts of active monomeric insulin to beavailable for postprandial injections.

In another embodiment, the insulin may contain an A and/or B chain ofaspart (also known as Novolog, Novo Nordisk). Insulin aspart is designedwith the single replacement of the amino acid proline by aspartic acidat position 28 of the human insulin B chain. This modification helpsblock the formation for insulin hexamers, creating a faster actinginsulin.

In yet another embodiment, the insulin may contain an A and/or B chainof glulisine (also known as Apidra, Sanofi-Aventis). Insulin glulisineis a short acting analog created by substitution of asparagine atposition 3 by lysine and lysine at position 29 by glutamine of humaninsulin B chain. Insulin glulisine has more rapid onset of action andshorter duration of action compared to regular human insulin.

In another embodiment, the insulin may contain an A and/or B chain ofglargine (also known as Lantus, Sanofi-Aventis). Insulin glarginediffers from human insulin in that the amino acid asparagine at position21 of the A chain is replaced by glycine and two arginines are added tothe C-terminus of the B-chain. Compared with bedtime neutral protamineHagedorn (NPH) insulin (an intermediate acting insulin), insulinglargine is associated with less nocturnal hypoglycemia in patients withtype 2 diabetes.

In yet another embodiment, the insulin may contain an A and/or B chainfrom detemir (also known as Levemir, Novo Nordisk). Insulin detemir is asoluble (at neutral pH) long-acting insulin analog, in which the aminoacid threonine at B30 is removed and a 14-carbon, myristoyl fatty acidis acetylated to the epsilon-amino group of LysB29. After subcutaneousinjection, detemir dissociates, thereby exposing the free fatty acidwhich enables reversible binding to albumin molecules. So at steadystate, the concentration of free unbound insulin is greatly reducedresulting in stable plasma glucose levels.

In some embodiments, the insulin may be a single-chain insulin analog(SIA) (e.g. as described in 6,630,438 and WO08/019368, which are herebyincorporated by reference in their entirety). Single-chain insulinanalogs encompass a group of structurally-related proteins wherein the Aand B chains are covalently linked by a polypeptide linker. Thepolypeptide linker connects the C-terminus of the B chain to theN-terminus of the A chain. The linker may be of any length so long asthe linker provides the structural conformation necessary for the SIA tohave a glucose uptake and insulin receptor binding effect. In someembodiments, the linker is about 5-18 amino acids in length. In otherembodiments, the linker is about 9-15 amino acids in length. In certainembodiments, the linker is about 12 amino acids long. In certainexemplary embodiments, the linker has the sequence KDDNPNLPRLVR (SEQ IDNO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21). However, it should beunderstood that many variations of this sequence are possible such as inthe length (both addition and deletion) and substitutions of amino acidswithout substantially compromising the effectiveness of the produced SIAin glucose uptake and insulin receptor binding activities. For example,several different amino acid residues may be added or removed fromeither end without substantially decreasing the activity of the producedSIA.

An exemplary single-chain insulin analog currently in clinicaldevelopment is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8).Albulin can be produced in yeast or in mammalian cells. It consists ofthe B and A chain of human insulin (100% identity to native humaninsulin) linked together by a dodecapeptide linker and fused to the NH₂terminals of the native human serum albumin. For expression andpurification of albulin, Duttaroy et al. constructed a synthetic geneconstruct encoding a single-chain insulin containing the B- and A-chainof mature human insulin linked together by a dodecapeptide linker usingfour overlapping primers and PCR amplification. The resulting PCRproduct was ligated in-frame between the signal peptide of human serumalbumin (HSA) and the NH₂ terminus of mature HSA, contained within apSAC35 vector for expression in yeast. In accordance with the presentinvention, the HSA component of abulin may be replaced with an ELPcomponent as described herein.

Thus, in one aspect, the present invention provides therapeutic agentscomprising an elastic peptide and an insulin or functional analogthereof. For example, in certain embodiments, the insulin is a mammalianinsulin, such as human insulin or porcine insulin. In accordance withthe invention, the elastic peptide component may be coupled (e.g., viarecombinant fusion or chemical conjugation) to the insulin A chain, or Bchain, or both. The insulin may comprise each of chains A, B, and C (SEQID NOS: 51 and 52), or may contain a processed form, containing onlychains A and B. In some embodiments, chains A and B are connected by ashort linking peptide, to create a single chain insulin. The insulin maybe a functional analog of human insulin, including functional fragmentstruncated at the N-terminus and/or C-terminus (of either or both ofchains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, orabout 5 amino acids. Functional analogs may contain from 1 to 10 aminoacid insertions, deletions, and/or substitutions (collectively) withrespect to the native sequence (e.g., SEQ ID NOS 15 and 16), and in eachcase retaining the activity of the peptide. For example, functionalanalogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions,and/or substitutions (collectively) with respect to the native sequence(which may contain chains A and B, or chains A, B, and C). Such activitymay be confirmed or assayed using any available assay, including thosedescribed herein. In these or other embodiments, the insulin componenthas at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with each ofthe native sequences for chains A and B (SEQ ID NOS:15 and 16). Thedetermination of sequence identity between two sequences (e.g., betweena native sequence and a functional analog) can be accomplished using anyalignment tool, including Tatusova et al., Blast 2 sequences—a new toolfor comparing protein and nucleotide sequences FEMS Microbiol Lett.174:247-250 (1999). The insulin component may contain additionalchemical modifications known in the art.

In another aspect, the present invention provides methods for thetreatment or prevention of diabetes, including type I and II diabetes.The method comprises administering an effective amount of thetherapeutic agent comprising an elastic peptide (e.g., ELP) componentand an insulin (or functional analog thereof) component to a patient inneed thereof. Generally, the patient may be a human or non-human animal(e.g., dog, cat, cow, or horse) patient. Preferably, the patient ishuman.

To characterize the in vitro binding properties of an insulin analog oran elastic peptide-containing insulin analog, competition binding assaysmay be performed in various cell lines that express the insulin receptor(Jehle et al., 1996, Diabetologia 39: 421-432). For example, competitionbinding assays using CHO cells overexpressing the human insulin receptormay be employed. Insulin can also bind to the IGF-1 receptor with alower affinity than the insulin receptor. To determine the bindingaffinity of an ELP-containing insulin analog, a competition bindingassay can be performed using ¹²⁵1-labeled IGF-1 in L6 cells.

The activities of insulin include stimulation of peripheral glucosedisposal and inhibition of hepatic glucose production. The ability of anelastic peptide-containing insulin analog to mediate these biologicalactivities can be assayed in vitro using known methodologies. Forexample, the effect of an elastic peptide-containing analog on glucoseuptake in 3T3-L1 adipocytes can be measured and compared with that ofinsulin. Pretreatment of the cells with a biologically active analogwill generally produce a dose-dependent increase in 2-deoxyglucoseuptake. The ability of an elastic peptide-containing insulin analog toregulate glucose production may be measured in any number of cellstypes, for example, H4IIe hepatoma cells. In this assay, pretreatmentwith a biologically active analog will generally result in adose-dependent inhibition of the amount of glucose released.

Factor VII (VIIa)

In certain embodiments, the invention provides therapeutic agentscomprising an elastic peptide component coupled (e.g., via fusion orconjugation) to a Factor VII/VIIa. Coagulation is the biological processof blood clot formation involving many different serine proteases aswell as their essential cofactors and inhibitors. It is initiated byexposure of Factor VII (FVII) and Factor VIIa (FVIIa) to its membranebound cofactor, tissue factor (TF), resulting in production of Factor Xa(FXa) and more FVIIa. The process is propagated upon production ofFactor IXa (FIXa) and additional FXa that, upon binding with theirrespective cofactors FVIIIa and FVa, form platelet bound complexes,ultimately resulting in the formation of thrombin and a fibrin clot.Thrombin also serves to further amplify coagulation by activation ofcofactors such as FV and FVII and zymogens such as Factor XI. Moreover,thrombin activates platelets leading to platelet aggregation, which isnecessary for the formation of a hemostatic plug.

Factor VII circulates in the blood in a zymogen form, and is convertedto its active form, Factor VIIa, by either factor IXa, factor Xa, factorXIIa, or thrombin by minor proteolysis. Factor VIIa is a two-chain, 50kilodalton (kDa) plasma serine protease. The active form of the enzymecomprises a heavy chain (254 amino acid residues) containing a catalyticdomain and a light chain (152 residues) containing 2 epidermal growthfactor (EGF)-like domains. The mature factor VII/VIIa that circulates inplasma is composed of 406 amino acid residues (SEQ ID NO: 33). The lightand heavy chains are held together by a disulfide bond.

As noted above, Factor VIIa is generated by proteolysis of a singlepeptide bond from its single chain zymogen, Factor VII, which is presentat approximately 0.5 μg/ml in plasma. The conversion of zymogen FactorVII into the activated two-chain molecule occurs by cleavage of aninternal peptide bond. In human Factor VII, the cleavage site is atArg152-IIe153 (Hagen et al., 1986, PNAS USA 83: 2412-6).

“Factor VII/VIIa” as used in this application means a product consistingof either the unactivated form (factor VII) or the activated form(factor VIIa) or mixtures thereof. “Factor VII/VIIa” within the abovedefinition includes proteins that have an amino acid sequence of nativehuman factor VII/VIIa. It also includes proteins with a slightlymodified amino acid sequence, for instance, a modified N-terminal endincluding N-terminal amino acid deletions or additions so long as thoseproteins substantially retain the activity of factor VIIa. “Factor VII”within the above definition also includes natural allelic variationsthat may exist and occur from one individual to another. Also, degreeand location of glycosylation or other post-translation modificationsmay vary depending on the chosen host cells and the nature of the hostcellular environment.

In the presence of calcium ions, Factor VIIa binds with high affinity toTF. TF is a 263 amino acid residue glycoprotein composed of a 219residue extracellular domain, a single transmembrane domain, and a shortcytoplasmic domain (Morrissey et al., 1987, Cell 50: 129-35). The TFextracellular domain is composed of two fibronectin type III domains ofabout 105 amino acids each. The binding of FVIIa is mediated entirely bythe TF extracellular domain (Muller et al., 1994, Biochem. 33:10864-70).Residues in the area of amino acids 16-26 and 129-147 contribute to thebinding of FVIIa as well as the coagulant function of the molecule.Residues Lys20, Trp45, Asp58, Tyr94, and Phe140 make a largecontribution (1 kcal/mol) to the free energy (ΔG) of binding to FVIIa.

TF is expressed constitutively on cells separated from plasma by thevascular endothelium. Its expression on endothelial cells and monocytesis induced by exposure to inflammatory cytokines or bacteriallipopolysaccharides (Drake et al., 1989, J. Cell Biol. 109: 389). Upontissue injury, the exposed extracellular domain of TF forms a highaffinity, calcium dependent complex with FVII. Once bound to TF, FVIIcan be activated by peptide bond cleavage to yield serine proteaseFVIIa. The enzyme that catalyzes this step in vivo has not beenelucidated, but in vitro FXa, thrombin, TF:FVIIa and FIXa can catalyzethis cleavage. FVIIa has only weak activity upon its physiologicalsubstrates FX and FIX whereas the TF:FVIIa complex rapidly activates FXand FIX.

The TF:FVIIa complex constitutes the primary initiator of the extrinsicpathway of blood coagulation. The complex initiates the extrinsicpathway by activation of FX to Factor Xa (FXa), FIX to Factor IXa(FIXa), and additional FVII to FVIIa. The action of TF:FVIIa leadsultimately to the conversion of prothrombin to thrombin, which carriesout many biological functions. Among the most important activities ofthrombin is the conversion of fibrinogen to fibrin, which polymerizes toform a clot. The TF:FVIIa complex also participates as a secondaryfactor in extending the physiological effects of the contact activationsystem.

The initiation and subsequent regulation of coagulation is complex,since maintenance of hemostasis is crucial for survival. There is anexquisite balance between hemostasis (normal clot formation anddissolution) and thrombosis (pathogenic clot formation). Seriousclinical conditions involving aberrations in coagulation include deepvein thrombosis, myocardial infarction, pulmonary embolism, stroke anddisseminated intravascular coagulation (in sepsis). There are also manybleeding coagulopathies where there is insufficient clot formation.These include hemophilia A (FVIII deficiency) or hemophilia B (FIXdeficiency), where procoagulant therapy is required. The challenge inthis therapeutic area is to operate in the narrow window between toomuch and too little coagulation.

The use of exogenous FVIIa as a therapeutic agent has been shown toinduce hemostasis in patients with hemophilia A and B (Hedner, 2001,Seminars Hematol. 38 (suppl. 12): 43-7; Hedner, 2004, Seminars Hematol.41 (suppl. 1): 35-9). It also has been used to treat bleeding inpatients with liver disease, anticoagulation-induced bleeding, surgery,thrombocytopenia, thrombasthenia, Bemard-Soulier syndrome, vonWillebrand disease, and other bleeding disorders (See e.g. Roberts etal., 2004, Blood 104: 3858-64).

Commercial preparations of human recombinant FVIIa are sold asNovoSeven.™ NovoSeven™ is indicated for the treatment of bleedingepisodes in hemophilia A or B patients and is the only recombinant FVIIaeffective for bleeding episodes currently available. A circulatingrecombinant FVIIa half-life of 2.3 hours was reported in “Summary Basisfor Approval for NovoSeven™” FDA reference number 96-0597. Moreover, thehalf-life of recombinant FVIIa is shorter in pediatric patients (˜1.3hours), suggesting that higher doses of recombinaint FVIIa may berequired in this population (Roberts et al., 2004, Blood 104: 3858-64).Accordingly, relatively high doses and frequent administration arenecessary to reach and sustain the desired therapeutic or prophylacticeffect. As a consequence, adequate dose regulation is difficult toobtain and the need of frequent intravenous administrations imposesrestrictions on the patient's way of living.

A molecule with a longer circulation half-life would decrease the numberof necessary administrations. Given the frequent injections associatedwith currently available FVIIa therapy and the potential for obtainingmore optimal therapeutic FVIIa levels with concomitant enhancedtherapeutic effect, there is a clear need for improved FVII orFVIIa-like molecules with a longer half-life in vivo.

Recombinant human coagulation factor VIIa (rFVIIa, NovoSeven; NovoNordisk A/S, Copenhagen, Denmark) has proven to be efficacious for thetreatment of bleeding episodes in hemophilia patients with inhibitors. Asmall fraction of patients may be refractory to rFVIIa treatment andcould potentially benefit from genetically modified FVIIa molecules withincreased potencies. To this end, FVIIa analogs with increased intrinsicactivity have been investigated that exhibit superior hemostaticprofiles in vitro (see e.g. WO02/077218 or WO05/074975, which are herebyincorporated by reference in their entirety, and Tranholm et al., 2003,Blood 102(10): 3615-20, which is also incorporated by reference). Theseanalogs may also be used as more efficacious hemostatic agents in otherindications where efficacy of rFVIIa has been observed, including inthrombocytopenia and trauma.

Thus, in some embodiments, the Factor VIIa analog that may be used inaccordance with the invention is as described in WO02/077218 orWO05/074975. For example, the FVIIa analog may have a glutaminesubstituted for methionine at position 298 (i.e. M298Q-FVIIa). Incertain exemplary embodiments, the FVIIa analog contains two additionalmutations, valine at position 158 replaced by aspartic acid and glutamicacid at position 296 replaced by valine (i.e. V158D/E296V/M298Q-FVIIa).Additionally or alternatively, the Factor VIIa analog may have analanine residue substitution for lysine at position 337 (i.e.V158D/E296V/M298Q/K337A-FVIIa). In still other embodiments, the FactorVIIa analog has a substitution or insertion selected from Q250C; P406C;and 407C, wherein a cysteine has also been introduced in the C-terminalsequence (see, e.g. U.S. Pat. No. 7,235,638, which is herebyincorporated by reference in its entirety). The Factor VIIa analog mayfurther comprise a substitution or insertion at one or more of positions247, 260, 393, 396, and/or 405.

In these or other embodiments, the Factor VIIa analog comprises asubstitution relative to the sequence of native Factor VIIa selectedfrom: (a) a substitution of Lys157 with an amino acid selected from thegroup consisting of Gly, Val, Ser, Thr, Asp, and Glu; (b) a substitutionof Lys337 with ah amino acid selected from the group consisting of Ala,Gly, Val, Ser, Thr, Gin, Asp, and Glu; (c) a substitution of Asp334 withany amino acid other than Ala or Asn; and (d) a substitution of Ser336with any amino acid other than Ala or Cys (see e.g. U.S. Pat. No.7,176,288, which is hereby incorporated by reference in its entirety).Additionally or alternatively, the Factor VIIa analog comprises asubstitution of the Leu at position 305 of Factor VII with an amino acidresidue selected from the group consisting of Val, Ile, Met, Phe, Trp,Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and Gln (seee.g. U.S. Pat. No. 6,905,683, which is hereby incorporated by referencein its entirety).

Thus, in one aspect, the present invention provides therapeutic agentscomprising an elastic peptide, e.g., an elastin-like peptide (ELP) and aFactor VII/VIIa, or functional analog thereof. For example, in certainembodiments, the Factor VII/VIIa is human Factor VII/VIIa (e.g., SEQ IDNO: 33). The Factor VII/VIIa may be a functional analog of human FactorVII/VIIa, including functional fragments truncated at the N-terminusand/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, orabout 5 amino acids. Functional analogs may contain from 1 to 10 aminoacid insertions, deletions, and/or substitutions (collectively) withrespect to the native sequence (e.g., SEQ ID NO: 33), and in each caseretaining the activity of the peptide. For example, such analogs mayhave from 1 to about 5 amino acid insertions, deletions, and/orsubstitutions (collectively) with respect to the native full lengthsequence, or with respect to one or both of the heavy and light chains.Such activity may be confirmed or assayed using any available assay,including those described herein. In these or other embodiments, theFactor VII/VIIa component has at least about 75%, 80%, 85%, 90%, 95%, or98% identity with the native sequence (SEQ ID NO:33). The determinationof sequence identity between two sequences (e.g., between a nativesequence and a functional analog) can be accomplished using anyalignment tool, including Tatusova et al., Blast 2 sequences—a new toolfor comparing protein and nucleotide sequences, FEMS Microbiol Left.174:247-250 (1999).

In exemplary embodiments, the FactorVII-ELP fusion has the amino acidsequence of SEQ ID NO:58. SEQ ID NO:58 further comprises a TEV proteasecleavage site between the FactorVII and ELP sequences, which may bebeneficial for removing the ELP sequence post expression where desired.However, in accordance with the invention, the tev sequence may beentirely removed, or replaced with another linking sequence as disclosedherein.

In another aspect, the present invention provides methods for thetreatment or prevention of bleeding-related disorders. The methodcomprises administering an effective amount of the therapeutic agentcomprising an elastic peptide and a Factor VII/VIIa or functional analogthereof to a patient in need. In certain embodiments, thebleeding-related disorder is one or more of hemophilia (A or B),post-surgical bleeding, anticoagulation-induced bleeding,thrombocytopenia, Factor VII deficiency, Factor XI deficiency, bleedingin patients with liver disease, thrombasthenia, Bemard-Soulier syndrome,von Willebrand disease, and intracranial hemorrhage. Generally, thepatient is a human or non-human animal (e.g., dog, cat, cow, or horse)patient. Preferably, the patient is human.

To characterize the in vitro binding properties of a suspected FactorVII/VIIa analog, or an elastic peptide-containing Factor VIIa analog, TFbinding assays can be performed as described previously (See, e.g.,Chaing et al., 1994, Blood 83(12): 3524-35). Briefly, recombinant humanTF can be coated onto Immulon II plates in carbonate antigen bufferovernight at 4° C. BSA is also coated onto the plates for use as acontrol. Elastic peptide-containing Factor VIIa analogs may be added atvarious concentrations in TBS-T buffer. After several washes,monospecific polyclonal rabbit anti-human FVIIa sera is added andincubated for approximately an hour at room temperature. Next, goatanti-rabbit IgG conjugated to alkaline phosphatase is added, followed bythe alkaline phosphatase substrate PNPP, which is used for detection.After subtraction of background, the absorbance at ˜405 nm is taken tobe directly proportional to the degree of Factor VIIa binding to theimmobilized TF. These values can then be compared to control plasmacontaining Factor VIIa.

The clotting ability of a Factor VII/VIIa analog or an elasticpeptide-containing Factor VIIa analog can be measured in human FVIIdeficient plasma. In this assay, the elastic peptide-containing FactorVIIa analog diluted to varying concentrations directly into FVIIdeficient plasma. In a coagulometer, one part plasma±a FVIIa analog canbe mixed with 2 parts Innovin™ (Dade, Miami, Fla.) prothrombin timereagent (recombinant human tissue factor with phospholipids and CaCl₂).Clot formation is detected optically and time to clotting measured.Clotting time (seconds) is compared to the mean clotting time ofFVII-deficient plasma alone and plotted as the fractional clotting timeversus FVIIa analog concentration.

Therapeutic Proteins

The present invention further provides therapeutic agents comprising anelastic peptide component and at least one therapeutic protein selectedfrom Table 1. The elastic peptide (e.g., ELP) component and therapeuticprotein may be coupled by recombinant fusion or chemical conjugation asdescribed herein. Such therapeutic proteins are listed in Table 1 byprotein name and GeneSeq Accession No. The amino acid sequence of eachTherapeutic Protein, which is known in the art, is hereby incorporatedby reference for each Therapeutic Protein listed in Table 1. Suchtherapeutic proteins are further described in US patent or PCTpublications that are also listed in Table 1, and such US patent and PCTpublications are hereby incorporated by reference, especially withrespect to the structure of such therapeutic proteins and describedfunctional analogs.

Table 1 further describes the biological activity of each listedTherapeutic Protein, as well as an exemplary assay for determining theactivity of functional analogs or agents of the invention (e.g., fusionwith an elastic peptide component). Generally, functional analogs oftherapeutic proteins listed in Table 1 may include functional fragmentstruncated at the N-terminus and/or C-terminus by from 1 to 10 aminoacids, including by 1, 2, 3, 4 or about 5 amino acids. Functionalanalogs may contain from 1 to 10 amino acid insertions, deletions,and/or substitutions (collectively) with respect to the base sequence(e.g., as listed in Table 1), and in each case retaining the full orpartial biological activity (as listed in Table 1) of the therapeuticprotein. For example, functional analogs may have 1, 2, 3, 4, or 5 aminoacid insertions, deletions, and/or substitutions (collectively) withrespect to the base sequence. Such activity may be confirmed or assayedusing any available assay, including those described in the Table. Inthese or other embodiments, the therapeutic protein has at least about75%, 80%, 85%, 90%, 95%, or 98% identity with the corresponding basesequence. The molecules may further comprise additional chemicalmodifications known for each in the art.

In some embodiments, the therapeutic protein (e.g., as selected fromTable 1) has a size of less than about 25 kDa, or less than about 10kDa, or less than about 5 kDa, and the corresponding therapeutic agentof the invention (e.g., comprising the ELP component) has a molecularweight of less than about 60 kDa, 55 kDa, 50 kDa, or 40 kDa.

Table 1 further lists preferred indications for each therapeuticprotein, for which the corresponding therapeutic agent finds use, suchas in a method for treatment or prevention related to such indication.

TABLE 1 PCT/Patent Reference Exemplary (the patents Identifier and (thesequences publications listed in this listed in this column are eachcolumn are Exemplary Activity Assay hereby each hereby (the publicationslisted in this column Therapeutic incorporated by incorporated are eachhereby incorporated by Protein X reference) by reference) BiologicalActivity reference) Preferred Indication Y BMP-1 GeneSeq WO8800205 BMP1belongs to the transforming growth BMP-1 activity can be determinedusing Induction of Cartilage, Acession P80618 factor-beta (TGFB)superfamily. Bone the following assays known in the art: Nat Tissue andBone Growth, morphogenic proteins induce cartilage Genet. 2001 Jan;27(1): 84-8; Eur J and Diabetes and bone formation, play important roleBiochem 1996 Apr 1; 237(1): 295-302; J in nephrogesis, and play animportant Biol Chem, Vol. 274, Issue 16, 10897-10902, role in thedevelopment of many organs, Apr. 16, 1999; and Hogan, B. L. M. includinglung, heart, teeth, gut, skin, and (1996) Genes Dev. 10, 1580-1594.particularly the kidney. BMP-2 GeneSeq WO8800205 BMP-2 belongs to thetransforming BMP-2 activity can be determined using the Induction ofCartilage, Accession P80619 growth factor-beta (TGFB) superfamily.following assays known in the art: Nat Tissue and Bone Growth, Bonemorphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J andDiabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem,Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M.(1996) Genes Dev. 10, 1580-1594. BMP-2B GeneSeq U.S. Pat. No. 5,631,142BMP-2b belongs to the transforming BMP-2b activity can be determinedusing Induction of Cartilage, Accession W24850 growth factor-beta (TGFB)superfamily. the following assays known in the art: Nat Tissue and BoneGrowth, Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1):84-8; Eur J and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302;I Biol Cbcre, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan,B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-4 GeneSeq WO0020591 BMP-4belongs to the transforming BMP-4 activity can be determined using theInduction of Cartilage, Accession growth factor-beta (TGFB) superfamily.following assays known in the art: Nat Tissue and Bone Growth, B02796Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; EurJ and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J BiolChem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L.M. (1996) Genes Dev. 10, 1580-1594. BMP-5 GeneSeq WO0020591 BMP-5belongs to the transforming BMP-5 activity can be determined using theInduction of Cartilage, Accession growth factor-beta (TGFB) superfamily.following assays known in the art: Nat Tissue and Bone Growth, B02797Bone morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; EurJ and Diabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J BiolChem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L.M. (1996) Genes Dev. 10, 1580-1594. BMP-6 GeneSeq U.S. Pat. No.5,187,076 BMP-6 belongs to the transforming BMP-6 activity can bedetermined using the Induction of Cartilage, Accession growthfactor-beta (TGFB) superfamily. following assays known in the art: NatTissue and Bone Growth, R32904 Bone morphogenic protein induces boneGenet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902,Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594.Osteogenic GeneSeq WO973462 OP-1 belongs to the transforming growth OP-1activity can be determined using the Induction of Cartilage, Protein-1;OP-1; Accession factor-beta (TGFB) superfamily. Bone following assaysknown in the art: Nat Tissue and Bone Growth, BMP-7 W34783 morphogenicprotein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetesformation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274,Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) GenesDev. 10, 1580-1594. Osteogenic GeneSeq WO9406399 OP-2 belongs to thetransforming growth OP-2 activity can be determined using the Inductionof Cartilage, Protein-2 Accession R57973 factor-beta (TGFB) superfamily.Bone following assays known in the art: Nat Tissue and Bone Growth,morphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J andDiabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem,Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M.(1996) Genes Dev. 10, 1580-1594. GDP-1 GeneSeq WO9406449 Members of theTGF-beta family of The effect of GDF-1 on signaling can be Developmentaldisorders, Accession proteins initiate cell signaling by binding assayedby treating Primary BAECs Induction of Cartilage, R60961 to heteromericreceptor complexes of transferred with a construct called p3TP- Tissueand Bone Growth, type I (TbetaRI) and type II (TbetaRII) Lux, containinga TGF-beta responsive and Diabetes serine/threonine kinase receptorspromoter fused to a reporter gene, and (reviewed by Massague, J. et al.(1994) measuring luciferase gene expression Trends Cell Biol. 4: 172178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al.(1994) Adv. Immunol. 55: 181-220). Activation of this heteromericreceptor complex occurs when TGF-beta binds to TbetaRII, which thenrecruits and phosphorylates TbetaRI. Activated TbetaRI then propagatesthe signal to downstream targets (Chen, F. and Weinberg, R. A. (1995)PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341 347).BMP-9 GeneSeq WO9533830 BMP-9 belongs to the transforming BMP-9 activitycan be determined using the Induction of Cartilage, Accession growthfactor-beta (TGFB) superfamily. following assays known in the art: NatTissue and Bone Growth, R86903 Bone morphogenic protein induces boneGenet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem 1996Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902,Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594.BMP-10 GeneSeq WO9426893 BMP-10 belongs to the transforming BMP-10activity can be determined using Induction of Cartilage, AccessionR66202 growth factor-beta (TGFB) superfamily. the following assays knownin the art: Nat Tissue and Bone Growth, Bone morphogenic protein inducesbone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetes formation. Biochem1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16,10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10,1580-1594. BMP-12 GeneSeq WO9516035 BMP-12 belongs to the transformingBMP-12 activity can be determined using Induction of Cartilage,Accession R78734 growth factor-beta (TGFB) superfamily. the followingassays known in the art: Nat Tissue and Bone Growth, Bone morphogenicprotein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J and Diabetesformation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274,Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) GenesDev. 10, 1580-1594. BMP-15 GeneSeq W09636710 BMP-15 belongs to thetransforming BMP-15 activity can be determined using Induction ofCartilage, Accession W11261 growth factor-beta (TGFB) superfamily. thefollowing assays known in the art: Nat Tissue and Bone Growth, Bonemorphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J andDiabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem,Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M.(1996) Genes Dev. 10, 1580-1594. BMP-17 GeneSeq WO9929718 BMP-17 belongsto the transforming BMP-17 activity can be determined using Induction ofCartilage, Accession Y17870 growth factor-beta (TGFB) superfamily. thefollowing assays known in the art: Nat Tissue and Bone Growth, Bonemorphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J andDiabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem,Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M.(1996) Genes Dev. 10, 1580-1594. BMP-18 GeneSeq WO9929718 BMP-18 belongsto the transforming BMP-18 activity can be determined using Induction ofCartilage, Accession Y17871 growth factor-beta (TGFB) superfamily. thefollowing assays known in the art: Nat Tissue and Bone Growth, Bonemorphogenic protein induces bone Genet. 2001 Jan; 27(1): 84-8; Eur J andDiabetes formation. Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem,Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M.(1996) Genes Dev. 10, 1580-1594. Inhibin alpha GeneSeq WO0020591 Theinhibin beta A subunit joins the alpha Tumor suppressor activity ofinhibin can be Tumor suppression. Accession B02806 subunit to form apituitary FSH secretion determined using assays known in the art:inhibitor. Inhibin has been shown to Matzuk et al., Nature 1992 Nov. 26:360 regulate gonadal stromal cell proliferation (6402); 313-9.negatively and to have tumour- suppressor activity. In addition, serumlevels of inhibin have been shown to reflect the size of granulosa-celltumors and can therefore be used as a marker for primary as well asrecurrent disease. Inhibin beta GeneSeq WO0020591 The inhibin beta Asubunit joins the alpha Tumor suppressor activity of inhibin can beTumor suppression. Accession subunit to form a pituitary FSH secretiondetermined using assays known in the art: H02808 inhibitor. Inhibin hasbeen shown to Matzuk et al., Nature 1992 Nov. 26: 360 regulate gonadalstromal cell proliferation (6402); 313-9. negatively and to have tumour-suppressor activity. In addition, serum levels of inhibin have beenshown to reflect the size of granulosa-cell tumors and can therefore beused as a marker for primary as well as recurrent disease. CerebusProtein GeneSeq WO9849296 Cerebus is believed to be involved in the BMPactivity, in the presence of the BMP Antagonist useful for Accessioninhibition of BMP activity antagonist Cerebus, can be determinedOsteosarcoma, abnormal W86032 using the following assays known in theart: bone growth. Nat Genet. 2001 Jan; 27(1): 84-8; Eur J Biochem 1996Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902,Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594.Soluble BMP GeneSeq WO9614579 Soluble BMP receptor kinase protein-3 isBMP activity, in the presence of the soluble BMP Antagonist useful forReceptor Kinase Accession involved in the binding of BMPs. Solubleantagonist BMP receptor kinase protein-3, Osteosarcoma, abnormalProtein-3 R95227 BMP receptor kinase protein-3 is useful can bedetermined using the following bone growth. as an antagonist for theinhibition of BMP assays known in the art: Nat Genet. 2001 activity.Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J BiolChem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L.M. (1996) Genes Dev. 10, 1580-1594. BMP Processing GeneSeq WO9741250BMPs belong to the transforming growth BMP activity, in the presence ofthe Furin, Bone formation or Enzyme Furin Accession factor-beta (TGFB)superfamily. Bone can be determined using the following RegenerationW36099 morphogenic protein induces bone assays known in the art: NatGenet. 2001 Abnormalities formation. Jan; 27(1): 84-8; Eur J Biochem1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16,10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10,1580-1594. TGF-beta 1 GeneSeq WO9216228 Members of the TGF-beta familyof The effect of TGF betas on signaling can Useful for treating cancerAccession proteins initiate cell signaling by binding be assayed bytreating Primary BAECs and to promote wound R29657 to heteromericreceptor complexes of transfected with a construct called p3TP- healing.type I (TbetaRI) and type II (TbetaRII) Lux, containing a TGF-betaresponsive serine/threonine kinase receptors promoter fused to areporter gene, and (reviewed by Massague, J. et al. (1994) measuringluciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K.(Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol.55: 181-220). Activation of this heteromeric receptor complex occurswhen TGF-beta. binds to TbetaRII, which then recruits and phosphorylatesTbetaRI. Activated TbetaRI then propagates the signal to downstreamtargets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana,J. L. et al. (1994) Nature 370: 341. TGF-beta 2 GeneSeq EP542679 Membersof the TGF-beta family of The effect of TGF betas on signaling canUseful for treating cancer Accession proteins initiate cell signaling bybinding be assayed by treating Primary BAECs and to promote wound R39659to heteromeric receptor complexes of transfected with a construct calledp3TP- healing. type I (TbetaRI) and type II (TbetaRII) Lux, containing aTGF-beta responsive serine/threonine kinase receptors promoter fused toa reporter gene, and (reviewed by Massague, J. et al. (1994) measuringluciferase gene expression Trends Cell Biol. 4: 172 178; Miyazono, K.(Wrana et al., 1994, Nature 370: 341-347). et al. (1994) Adv. Immunol.55: 181-220). Activation of this heteromeric receptor complex occurswhen TGF-beta. binds to TbetaRII, which then recruits and phosphorylatesTbetaRI. Activated TbetaRI then propagates the signal to downstreamtargets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana,J. L. et al. (1994) Nature 370: 341. ZTGF-beta 9 GeneSeq WO0015798Members of the TGF-beta family of The effect of TGF betas on signalingcan Useful for treating cancer Accession proteins initiate cellsignaling by binding be assayed by treating Primary BAECs and to promotewound Y70654 to heteromeric receptor complexes of transfected with aconstruct called p3TP- healing. type I (TbetaRI) and type II (TbetaRII)Lux, containing a TGF-beta responsive serine/threonine kinase receptorspromoter fused to a reporter gene, and (reviewed by Massague, J. et al.(1994) measuring luciferase gene expression Trends Cell Biol. 4: 172178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). et al.(1994) Adv. Immunol. 55: 181-220). Activation of this heteromericreceptor complex occurs when TGF-beta. binds to TbetaRII, which thenrecruits and phosphorylates TbetaRI. Activated TbetaRI then propagatesthe signal to downstream targets (Chen, F. and Weinberg. R. A. (1995)PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Anti-TGFbeta GB2305921 Members of the TGF-beta family of The effect of TGF betason signaling in the Useful for control of family antibodies proteinsinitiate cell signaling by binding presence of an anti-TGF betaantibody, can fibrosis, immune, and to heteromeric receptor complexes ofbe assayed by treating Primary BAECs inflammatory disease. type I(TbetaRI) and type II (TbetaRII) transfected with a construct calledp3TP- serine/threonine kinase receptors Lux, containing a TGF-betaresponsive (reviewed by Massague, J. et al. (1994) promoter fused to areporter gene, and Trends Cell Biol. 4: 172 178; Miyazono, K. measuringluciferase gene expression et al. (1994) Adv. Immunol. 55: 181-220).(Wrana et al., 1994, Nature 370: 341-347). Activation of thisheteromeric receptor complex occurs when TGF-beta. binds to TbetaRII,which then recruits and phosphorylates TbetaRI. Activated TbetaRI thenpropagates the signal to downstream targets (Chen, F. and Weinberg. R.A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341.Latent TGF beta GeneSeq WO0012551 Members of the TGF-beta family of Theeffect of TGF betas on signaling in the Useful for inhibiting tissuebinding protein II Accession proteins initiate cell signaling by bindingpresence of a TGF beta binding protein, or tumor growth. Y70552 toheteromeric receptor complexes of can be assayed by treating PrimaryBAECs type I (TbetaRI) and type II (TbetaRII) transfected with aconstruct called p3TP- serine/threonine kinase receptors Lux, containinga TGF-beta responsive (reviewed by Massague, J. et al. (1994) promoterfused to a reporter gene, and Trends Cell Biol. 4: 172 178; Miyazono, K.measuring luciferase gene expression et al. (1994) Adv. Immunol. 55:181-220). (Wrana et al., 1994, Nature 370: 341-347). Activation of thisheteromeric receptor complex occurs when TGF-beta. binds to TbetaRII,which then recruits and phosphorylates TbetaRI. Activated TbetaRI thenpropagates the signal to downstream targets (Chen, F. and Weinberg. R.A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341.MP52 GeneSeq WO9741250 Members of the TGF-beta family of The effect ofTGF betas on signaling can Bone formation or Accession proteins initiatecell signaling by binding be assayed by treating Primary BAECsRegeneration W36100 to heteromeric receptor complexes of transfectedwith a construct called p3TP- Abnormalities type I (TbetaRI) and type II(TbetaRII) Lux, containing a TGF-beta responsive serine/threonine kinasereceptors promoter fused to a reporter gene, and (reviewed by Massague,J. et al. (1994) measuring luciferase gene expression Trends Cell Biol.4: 172 178; Miyazono, K. (Wrana et al., 1994, Nature 370: 341-347). etal. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromericreceptor complex occurs when TGF-beta. binds to TbetaRII, which thenrecruits and phosphorylates TbetaRI. Activated TbetaRI then propagatesthe signal to downstream targets (Chen, F. and Weinberg. R. A. (1995)PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. b57Protein GeneSeq WO9837195 BMPs are involved in the induction of BMPactivity, in the presence of b57 BMP Antagonist useful for Accessionbone formation. Specific antagonists are protein, can be determinedusing the Osteosarcoma, abnormal W69293 useful is preventing thisactivity from following assays known in the art: Nat bone growth.occurring. Genet. 2001 Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1;237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 1089-10902, Apr. 16,1999; and Hogan, B. L. M. (1996) Genes Deve. 10, 1580-1594. ResistinGeneSeq WO0064920 This gene belongs to the family defined by Ability ofresistin to influence type II Type II diabetes and Accession mouse FIZZIand FIZZ3/Resistin genes. diabetes can be determined using assaysSyndrome X. W69293 The characteristic feature of this family is known inthe art: Pontoglio et al., J Clin the C-terminal stretch of 10 cysresidues Invest 1998 May 15; 101(10): 2215-22. with identical spacing.The mouse homolog of this protein is secreted by adipocytes, may be thehormone potantially linking obesity to type II diabetes. Galectin-4GeneSeq WO9703190 Galectins are a family of carbohydrate- Ability ofGalectin-4 polypeptides to bind Lactose intolerance. Accession bindingproteins characterized by an lactose can be determined using assaysW11841 affinity for beta-galactoside containing known in the art: Wada,et al., J Biol Chem glycoconjugates. 1997 Feb 28; 272(9): 6078-86.APM-I; ACRP-30; GeneSeq W00026363 ACPR30 gene is exclusively expressedin Ability of ACRP30 polypeptides to Obesity, Metabolic FamoxinAccession adipose tissue. ACRP30 is thought to influence obesity and fatoxidation can be disorders, Lipid Y71035 increase fatty acid oxidationby muscle determined using assays known in the art: Metabolism; Hormonetissue. Fruebis et al., Proc Nat'l Acad Sci USA Secretion. 2001 Feb 13;98(4): 2005-10. ACRP-30 GeneSeq WO0063376 ACPR30 gene is exclusivelyexpressed in Ability of ACRP30 homologue Obesity, Metabolic Homologue;Accession adipose tissue. ACRP30 is thought to polypeptides to influenceobesity and fat disorders, Lipid Complement B30234 increase fatty acidoxidation by muscle oxidation can be determined using assays Metabolism;Hormone Component Clq C tissue. known in the art: Fruebis et al., ProcNat'l Secretion. Acad Sci USA 2001 Feb 13; 98(4): 2005-10. Calpain-10aGeneSeq WO0023603 Calpain is believed to play a role in insulin Abilityof Calpain-10 to influence type II Diabetes mellitus; Accessionsecretion and insulin activity, and diabetes can be determined usingassays Regulation of Insulin Y79567 therefore may be useful in thetreatment known in the art: Pontoglio et al., J Clin secretory response;of type II diabetes. Invest 1998 May 15; 101(10): 2215-22. Insulinmediated glucose transport disorders. Calpain-10b GeneSeq WO0023603Calpain is believed to play a role in insulin Ability of Calpain-10 toinfluence type II Diabetes mellitus; Accession secretion and insulinactivity, and diabetes can be determined using assays Regulation ofInsulin Y79568 therefore may be useful in the treatment known in theart: Pontoglio et al., J Clin secretory response; of type II diabetes.Invest 1998 May 15; 101(10): 2215-22. Insulin mediated glucose transportdisorders. Calpain-10c GeneSeq WO0023603 Calpain is believed to play arole in insulin Ability of Calpain-10 to influence type II Diabetesmellitus; Accession secretion and insulin activity, and diabetes can bedetermined using assays Regulation of Insulin Y79569 therefore may beuseful in the treatment known in the art: Pontoglio et al., J Clinsecretory response; of type II diabetes. Invest 1998 May 15; 101(10):2215-22. Insulin mediated glucose transport disorders. PDGF-D GeneSeqWO0027879 Vascular Endothelial Growth Factor. Proliferation assay usingNR6R-3T3 cells Wound Healing; Accession (Rizzino 1988 Cancer Res. 48:4266). Atherosclermis. Y71130 FasL GeneSeq WO9936079 Activitiesassociated with apoptosis and Activity can be determined usingApoptosis-related Accession immune system functions. Apoptosis assaysknown in the art: disorders; Autoimmune Y28594 Walczak et al. (1996)EMBOJ 16: 5386-5397. disorders; Graft v-Host disorders. Chondro modulin-GeneSeq W00029579 Chondromodulin proteins are cartilage Ability ofChondromodulin-like protein to Antianglogenic agent; like proteinAccession proteins thought to confer resistance to inhibitvascularization can be determined Osteoblast proliferation Y71262anglogeneis, and thus are useful as anti- using assays known in the art:Hirakie et stimulator; prevents angiogenic agents that may have utilityin al., J Biol Chem 1997 Dec 19; vascularization of cartilage combatingcancer. 272(51): 32419-26. tissue; Useful to treat cancer. PatchedGeneSeq U.S. Pat. No. 5,837,538 Patched is a tumour-suppressor receptorAbility of soluble Patched to bind to and Receptor for HedgehogAccession for Sonic hedgehog (shh), which is a inhibit the activities ofshh can be cellular proliferation W72969 protein that controlsdevelopmental determined using assays known in the art: signalingmolecule. This patterning and growth. Stone et al., Nature 1996 Nov 14;receptor is useful as a 384(6605): 129-34. means of preventing cellularproliferation via the shh signaling pathway, thus useful for cancers.Patched-2 GeneSeq WO9953058 Patched is a tumour-suppressor receptorAbility of soluble Patched to bind to and Receptor for HedgehogAccession for Sonic hedgehog (shh), which is a inhibit the activities ofshh can be cellular proliferation Y43261 protein that controlsdevelopmental determined using assays known in the art: signalingmolecule. This patterning and growth. Stone et al., Nature 1996 Nov 14;receptor is useful as a 384(6605): 129-34. means of preventing cellularproliferation via the shh signaling pathway, thus useful for cancers.Maspin; Protease GeneSeq WO9405804 Maspin is a member of the serpinfamily of The inhibitory effects cf Maspin and other Tumor suppressorwhich is Inhibitor 5 Accession serine protease inhibitors that isthought protease inhibitors can be assayed using down-regulated inbreast R50938 to suppress tumor metastasis. methods known in the artsuch as a cancers. The maspin labeled protease substrate, for example,protein has tumour Universal Protease Substrate (casein, suppressing andinvasion resorufin-labeled): Roche Molecular suppressing activity.Biochemicals, Cat. No. 1080733. Endostatin GeneSeq WO0064946 Endostatinis believed to inhibit effects of The inhibitory effects of endostatincan be Anti-angiogenic activity. Accession capillary endothelial cellproliferation. assayed using assays disclosed by Cao et Useful in theprevention B28399 al. (1996) J. Biol. Chem. 271 29461-29467. and/ortreatment of cancers. aFGF; FGF-1 GeneSeq EP298723 Fibroblast GrowthFactor Proliferation assay using NR6R-3T3 cells Promotion of growth andAccession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells,such P94037 Examples 23 and 39 disclosed herein. as epithelial cells andkeratinocytes. Antagonists may be useful as anti- cancer agents. bFGF;FGF-2 GeneSeq FR2642086 Fibroblast Growth Factor Proliferation assayusing NR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988Cancer Res. 48: 4266); proliferation of cells, such R06685 Examples 23and 39 disclosed herein. as epithelial cells and keratinocytes.Antagonists may be useful as anti- cancer agents. FGF-3; INT-2 GeneSeqWO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3cells Promotion of growth and Accession (Rizzino 1988 Cancer Res. 48:4266); proliferation of cells, such R07824 Examples 23 and 39 disclosedherein. as epithelial cells and keratinocytes. Antagonists may be usefulas anti- cancer agents. FGF-4; HST-1; GeneSeq WO9503831 FibroblastGrowth Factor Proliferation assay using NR6R-3T3 cells Promotion ofgrowth and HBGF-4 Accession (Rizzino 1988 Cancer Res. 48: 4266);proliferation of cells, such R07825 Examples 23 and 39 disclosed herein.as epithelial cells and keratinocytes. Antagonists may be useful asanti- cancer agents. FGF-5 GeneSeq WO9730155 Fibroblast Growth FactorProliferation assay using NR6R-3T3 cells Promotion of growth andAccession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells,such W22600 Examples 23 and 39 disclosed herein. as epithelial cells andkeratinocytes. Antagonists may be useful as anti- cancer agents. FGF-6;Heparin GeneSeq EP613946 Fibroblast Growth Factor Proliferation assayusing NR6R-3T3 cells Promotion of growth and binding secreted Accession(Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, suchtransforming R58555 Examples 23 and 39 disclosed herein. as epithelialcells and factor-2 keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-8 GeneSeq WO9524928 Fibroblast Growth FactorProliferation assay using NR6R-3T3 cells Promotion of growth andAccession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells,such R80783 Examples 23 and 39 disclosed herein. as epithelial cells andkeratinocytes. Antagonists may be useful as anti- cancer agents. FGF-9;Gila GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assayusing NR6R-3T3 cells Promotion of growth and activating factor Accession(Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such R70822Examples 23 and 39 disclosed herein. as epithelial cells andkeratinocytes. Antagonists may be useful as anti- cancer agents. FGF-12;GeneSeq WO9635708 Fibroblast Growth Factor Proliferation assay usingNR6R-3T3 cells Promotion of growth and Fibroblast growth Accession(Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells, such factorhomologous W06309 Examples 23 and 39 disclosed herein. as epithelialcells and factor-1 keratinocytes. Antagonists may be useful as anti-cancer agents. FGF-15 GeneSeq WO9927100 Fibroblast Growth FactorProliferation assay using NR6R-3T3 cells Promotion of growth andAccession (Rizzino 1988 Cancer Res. 48: 4266); proliferation of cells,such Y08582 Examples 23 and 39 disclosed herein. as epithelial cells andkeratinocytes. Antagonists may be useful as anti- cancer agents. FGF-16GeneSeq WO9918128 Fibroblast Growth Factor Proliferation assay usingNR6R-3T3 cells Promotion of growth and Accession (Rizzino 1988 CancerRes. 48: 4266); proliferation of cells, such Y05474 Examples 23 and 39disclosed herein. as epithelial cells and keratinocytes. Antagonists maybe useful as anti- cancer agents. FGF-18 GeneSeq WO9927100 FibroblastGrowth Factor Proliferation assay using NR6R-3T3 cells Promotion ofgrowth and Accession (Rizzino 1988 Cancer Res. 48: 4266); proliferationof cells, such Y08590 Examples 23 and 39 disclosed herein. as epithelialcells and keratinocytes. Antagonists may be useful as anti- canceragents. fit-3 ligand GeneSeq EP627487 Stem Cell Progenitor Chemokineactivities can be determined Promotion of immune cell Accession usingassays known in the art: Methods in growth and/or R67541 MolecularBiology, 2000, vol. 138: differentiation. Chemokine Protocols. Editedby: A. E. I. Proudfoot, T. N. C. Wells, and C. A. Power. Humana PressInc., Totowa, NJ. VEGF-110 GeneSeq WO0013702 Promotes the growth and/orproliferation VEGF activity can be determined using Promotion of growthand Accession of endothelial cells. assays known in the art, such asthose proliferation of cells, such Y69417 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGB-121 GeneSeq WO0071713 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such B50432 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-138 GeneSeq WO9940197 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y43483 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-145 GeneSeq WO0013702 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y69413 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-162 GeneSeq W09940197 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y43484 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-165 GeneSeq WO0013702 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y69414 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-182 GeneSeq W09940197 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y43483 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-189 GeneSeq WO0013702 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y69415 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-206 GeneSeq W00013702 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such Y69416 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-D GeneSeq WO9807832 Promotes the growthand/or proliferation VEGF activity can be determined using Promotion ofgrowth and Accession of endothelial cells. assays known in the art, suchas those proliferation of cells, such W53240 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. VEGF-E; VEGF-X GeneSeq W09947677 Promotes thegrowth and/or proliferation VEGF activity can be determined usingPromotion of growth and Accession of endothelial cells. assays known inthe art, such as those proliferation of cells, such Y33679 disclosed inInternational Publication No. as vascular endothelial WO0045835, forexample. cells. Antagonists may be useful as anti-angiogenic agents, andmay be applicable for cancer. VEGF Receptor; GeneSeq WO9831794 Receptorfor VEGF polypeptides VEGF activity, in the presence of flk-1 VEGFReceptor. Fusion KDR; flk-1 Accession polypeptides, can be determinedusing protein with the W69679 assays known in the art, such as thoseextracellular domain is disclosed in International Publication No.useful as an anti- WO0045835, for example. angiogenic agent. Antagonistsmay be useful in the promotion of angiogenesis. Soluble VEGF GeneSeqU.S. Pat. No. 5,712,380 Receptor for VEGF polypeptides VEGF activity, inthe presence of VEGF VEGF Receptor. Fusion Receptor Accession Receptorpolypeptides, can be determined protein with the W47037 using assaysknown in the art, such as extracellular domain is those disclosed inInternational useful as an anti- Publication No. WO0045835, for example.angiogenic agent. Antagonists may be useful in the promotion ofangiogenesis. flt-1 GeneSeq WO0021560 Receptor for VEGF polypeptidesVEGF activity, in the presence of flt-1 VEGF Receptor. Fusion Accessionpolypeptides, can be determined using protein with the Y70751 assaysknown in the art, such as those extracellular domain is disclosed inInternational Publication No. useful as an anti- WO0045835, for example.angiogenic agent. Antagonists may be useful in the promotion ofangiogenesis. VEGF R-3; flt-4 GeneSeq WO0058511 Receptor for VEGFpolypeptides VEGF activity, in the presence of flt-4 VEGF Receptor.Fusion Accession polypeptides, can be determined using protein with theB29047 assays known in the art, such as those extracellular domain isdisclosed in International Publication No. useful as an anti- WO0045835,for example. angiogenic agent. Antagonists may be useful in thepromotion of angiogenesis. Neuropilin-1 GeneSeq WO9929858 VascularEndothelial Growth Factor VEGF activity can be determined usingPromotion of growth and Accession assays known in the art, such as thoseproliferation of cells, such Y06319 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. Neuropilin-2 GeneSeq WO9929858 VascularEndothelial Growth Factor VEGF activity can be determined usingPromotion of growth and Accession assays known in the art, such as thoseproliferation of cells, such Y03618 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. Human fast twitch GeneSeq W09730085 Troponins arecontractile proteins that are Ability of soluble Troponins to inhibitAnti-angiogenesis skeletal muscle Accession thought to inhibitangiogencsis. High anglogenesis can be determined using troponin CW22597 levels may contribute to the difficulty assays known in the art:.Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar 16;96(6): 2645-50. ischemic myocardium after cardiovascular injury. Humanfast twitch GeneSeq W09730085 Troponins are contractile proteins thatare Ability of soluble Troponins to inhibit Anti-angiogenesis skeletalmuscle Accession thought to inhibit angiogencsis. High anglogenesis canbe determined using troponin I W18054 levels may contribute to thedifficulty assays known in the art:. Proc Natl Acad encountered inrevascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemicmyocardium after cardiovascular injury. Human fast twitch GeneSeqW09730085 Troponins are contractile proteins that are Ability of solubleTroponins to inhibit Anti-angiogenesis skeletal muscle Accession thoughtto inhibit angiogencsis. High anglogenesis can be determined usingtroponin T W22599 levels may contribute to the difficulty assays knownin the art:. Proc Natl Acad encountered in revascularizing the Sci USA1999 Mar 16; 96(6): 2645-50. ischemic myocardium after cardiovascularinjury. fragment. GeneSeq W09719955 Troponins are contractile proteinsthat are Ability of soluble Troponins to inhibit Anti-angiogenesismyofibrillar protein Accession thought to inhibit angiogencsis. Highanglogenesis can be determined using troponin I W18053 levels maycontribute to the difficulty assays known in the art:. Proc Natl Acadencountered in revascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50.ischemic myocardium after cardiovascular injury. myofibrillar proteinGeneSeq W09719955 Troponins are contractile proteins that are Ability ofsoluble Troponins to inhibit Anti-angiogenesis troponin I Accessionthought to inhibit angiogencsis. High anglogenesis can be determinedusing W18054 levels may contribute to the difficulty assays known in theart:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury.Troponin peptides GeneSeq WO9933874 Troponins are contractile proteinsthat are Ability of soluble Troponins to inhibit Anti-angiogenesisAccessions thought to inhibit angiogencsis. High anglogenesis can bedetermined using Y29581, Y29582, levels may contribute to the difficultyassays known in the art:. Proc Natl Acad Y29583, Y29584, encountered inrevascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. Y29585, andischemic myocardium after cardiovascular Y29586 injury. Human fasttwitch GeneSeq WO0054770 Troponins are contractile proteins that areAbility of soluble Troponins to inhibit Anti-angiogenesis skeletalmuscle Accession thought to inhibit angiogencsis. High anglogenesis canbe determined using Troponin subunit C B00134 levels may contribute tothe difficulty assays known in the art:. Proc Natl Acad encountered inrevascularizing the Sci USA 1999 Mar 16; 96(6): 2645-50. ischemicmyocardium after cardiovascular injury. Human fast twitch GeneSeqWO0054770 Troponins are contractile proteins that are Ability of solubleTroponins to inhibit Anti-angiogenesis skeletal muscle Accession thoughtto inhibit angiogencsis. High anglogenesis can be determined usingTroponin subunit I B00135 levels may contribute to the difficulty assaysknown in the art:. Proc Natl Acad Protein encountered in revascularizingthe Sci USA 1999 Mar 16; 96(6): 2645-50. ischemic myocardium aftercardiovascular injury. Human fast twitch GeneSeq WO0054770 Troponins arecontractile proteins that are Ability of soluble Troponins to inhibitAnti-angiogenesis skeletal muscle Accession thought to inhibitangiogencsis. High anglogenesis can be determined using Troponin subunitT B00136 levels may contribute to the difficulty assays known in theart:. Proc Natl Acad encountered in revascularizing the Sci USA 1999 Mar16; 96(6): 2645-50. ischemic myocardium after cardiovascular injury.Activator Inbibitor- GeneSeq WO9013648 PAIs are believed to play a rolein cancer, Methods that measure plasminogen Anti-angiogenesis; blood- 1;PAI-1 Accession and cardiovascular disease and blood- activatorinhibitor (PAI) activity are known clotting disorders. R08411 clottingdisorders. in the art, for example, assay the ability of PAI to inhibittissue plasminogen activator (tPA) or urokinase (uPA): J Biochem BiophysMethods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2):141-6. Methods that measure anti-angiogenesis activity are known in theart, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50.Plasminogen GeneSeq DE3722673 PAIs are believed to play a role incancer, Methods that measure plasminogen Anti-angiogenesis; blood-Activator Inhibitor- Accession and cardiovascular disease and blood-activator inhibitor (PAI) activity are known clotting disorders. 2;PAI-2 P94160 clotting disorders. in the art, for example, assay theability of PAI to inhibit tissue plasminogen activator (tPA) orurokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40,Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measureanti-angiogenesis activity are known in the art, for example, Proc NatlAcad Sci USA 1999 Mar 16; 96(6): 2645-50. Activator Inhibitor- GeneSeqWO9102057 PAIs are believed to play a role in cancer, Methods thatmeasure plasminogen Anti-angiogenesis; blood- 2; PAI-2 Accession andcardiovascular disease and blood- activator inhibitor (PAI) activity areknown clotting disorders. R10921 clotting disorders. in the art, forexample, assay the ability of PAI to inhibit tissue plasminogenactivator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methodsthat measure anti-angiogenesis activity are known in the art, forexample, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Human PAI-1GeneSeq WO9105048 PAIs are believed to play a role in cancer, Methodsthat measure plasminogen Anti-angiogenesis; blood- mutants Accessionsand cardiovascular disease and blood- activator inhibitor (PAI) activityare known clotting disorders. R11755, R11756, clotting disorders. in theart, for example, assay the ability of R11757, R11758, PAI to inhibittissue plasminogen activator R11759, R11760, (tPA) or urokinase (uPA): JBiochem R11761, R11762 Biophys Methods 2000 Sep 11; 45(2): 127-40, andR11763 Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measureanti-angiogenesis activity are known in the art, for example, Proc NatlAcad Sci USA 1999 Mar 16; 96(6): 2645-50. CXCR3; CXC GeneSeq WO0018431Chemokines are a family of related small, Chemokine activities can bedetermined Soluble CXCR3 Accession secreted proteins involved inbiological using assays known in the art: Methods in polypeptides may beuseful Y79372 processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: for inhibiting chemokine angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot,activities and viral infection. Members of this family are involved in aT. N. C. Wells, and C. A. Power. similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. Modified Rantes GeneSeqWO9737005 Chemokines are a family of related small, Chemokine activitiescan be determined Immune disorders. Accession secreted proteins involvedin biological using assays known in the art: Methods in W38129 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. RANTES GeneSeq EP905240Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders. Accession secreted proteins involved inbiological using assays known in the art: Methods in Y05299 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. MCI-Ia GeneSeq WO9509232Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders. Accession secreted proteins involved inbiological using assays known in the art: Methods in R73914 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. MCP-Ib GeneSeq WO9929728Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders. Accession secreted proteins involved inbiological using assays known in the art: Methods in Y26176 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. MCP-I receptor GeneSeqWO9519436 Chemokines are a family of related small, Chemokine activitiescan be determined Soluble MCP-1 Receptor Accession secreted proteinsinvolved in biological using assays known in the art: Methods inpolypeptides may be useful R79165 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: for inhibiting chemokineangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, activities and viral infection. Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ. includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. MCP-3 GeneSeq W09509232 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders.Accession secreted proteins involved in biological using assays known inthe art: Methods in R73915 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJ.including inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. MCP-4 receptor GeneSeq W09809171 Chemokines are a family ofrelated small, Chemokine activities can be determined Soluble MCP-4Receptor Accession secreted proteins involved in biological using assaysknown in the art: Methods in polypeptides may be useful W56689 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: forinhibiting chemokine angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, activities and viralinfection. Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ. including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. RANTES receptor GeneSeq U.S. Pat. No.5,652,133 Chemokines are a family of related small, Chemokine activitiescan be determined Soluble RANTES Receptor Accession secreted proteinsinvolved in biological using assays known in the art: Methods inpolypeptides may be useful W29588 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: for inhibiting chemokineangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, activities and viral infection. Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ. includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. CCR5 variant GeneSeq WO9854317 Chemokines are a family ofrelated small, Chemokine activities can be determined Soluble CCR5polypeptides Accession secreted proteins involved in biological usingassays known in the art: Methods in may be useful for inhibiting W88238processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:chemokine activities and angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, viral infection.Members of this family are involved in a T. N. C. Wells, and C. A.Power. similarly diverse range of pathologies Humana Press Inc., Totowa,NJ. including inflammation, allergy, tissue rejection, viral infection,and tumor biology. The chemokines exert their effects by acting on afamily of seven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. CCR7 GeneSeq U.S. Pat. No. 6,153,441 Chemokines are a familyof related small, Chemokine activities can be determined Soluble CCR7polypeptides Accession secreted proteins involved in biological usingassays known in the art: Methods in may be useful for inhibiting B50859processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:chemokine activities and angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, viral infection.Members of this family are involved in a T. N. C. Wells, and C. A.Power. similarly diverse range of pathologies Humana Press Inc., Totowa,NJ. including inflammation, allergy, tissue rejection, viral infection,and tumor biology. The chemokines exert their effects by acting on afamily of seven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. CXC3 GeneSeq WO9727299 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders.Accession secreted proteins involved in biological using assays known inthe art: Methods in W23345 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJ.including inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Eotaxin GeneSeq WO9700960 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders.Accession secreted proteins involved in biological using assays known inthe art: Methods in W10099 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJ.including inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Neurotactin GeneSeq U.S. Pat. No. 6,013,257 Neurotactin mayplay a role in Chemotactic leukocyte migration assays Immune disorders.Accessions WO9742224 chemotactic leukocyte migration and brain are knownin the art, for example: J. Y77537, W34307, inflammation processes.Immunol. Methods 33, ((1980)); Nature Y53259, and, 1997 Jun 5;387(6633): 611-7. Y77539 Human CKbeta-9 GeneSeq U.S. Pat. No. 6,153,441Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders. Accession secreted proteins involved inbiological using assays known in the art: Methods in B50860 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. Lymphotactin GeneSeqWO0073320 Chemokines are a family of related small, Chemokine activitiescan be determined Immune disorders. Accession secreted proteins involvedin biological using assays known in the art: Methods in B50052 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G. MIP-3alpha GeneSeq WO9801557 Chemokines are a family of related small,Chemokine activities can be determined Immune disorders. Accessionsecreted proteins involved in biological using assays known in the art:Methods in W44398 processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ. includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G. MIP-3 beta GeneSeq WO9801557 Chemokines are afamily of related small, Chemokine activities can be determined Immunedisorders. Accession secreted proteins involved in biological usingassays known in the art: Methods in W44399 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ. including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G. MIP-Gamma GeneSeq WO9504158Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders. Accession secreted proteins involved inbiological using assays known in the art: Methods in R70798 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G. Stem CellGeneSeq WO9104274 Chemokines are a family of related small, Chemokineactivities can be determined Hematopoietic growth Inhibitory Accessionsecreted proteins involved in biological using assays known in the art:Methods in factors. Factor R11553 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJ.including inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G. thrombopoietin GeneSeq WO9521920Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed toHematopoietic growth Accession regulation of the growth anddifferentiation determine regulation of growth and factors. R79905 ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. c-kit ligand; GeneSeq EP992579 and C-kit liganis thought to stimulate the Chemokine activities can be determinedHematopoietic growth SCF; Mast cell Accession EP676470 proliferation ofmast cells, and is able to using assays known in the art: Methods infactors. growth factor; Y53284, R83978 augment the proliferation of bothmyeloid Molecular Biology, 2000, vol. 138: MGF; and R83977 and lymphoidhematopoietic progenitors in Chemokine Protocols. Edited by: A. E. I.Proudfoot, Fibrosarcoma- bone marrow culture. C-kit ligand is also T. N.C. Wells, and C. A. Power. derived stem though to act synergisticallywith other Humana Press Inc., Totowa, NJ. cell factor cytokines.Platelet derived GeneSeq WO0066736 Vascular Endothelial Growth FactorVEGF activity can be determined using Promotion of growth and growthfactor Accession B48653 assays known in the art, such as thoseproliferation of cells, such disclosed in International Publication No.as vascular endothelial WO0045835, for example. cells. Antagonists maybe useful as anti-angiogenic agents, and may be applicable for cancer.Melanoma GeneSeq WO9503328 Melanoma inhibiting protein has Tumorsuppressor activity of melanoma Cancer; melanoma inhibiting proteinAccession R69811 melanoma-inhibiting activity and can be inhibitingprotein can be determined using used to treat cancer (melanoma, assaysknown in the art: Matzuk et al., glioblastoma, neuroblastoma, small cellNature 1992 Nov 26; 360(6402): 313-9. lung cancer, neuroectodermaltumors) or as an immunosuppressant (it inhibits IL-2 orphytohaemagglutinin induced proliferation of peripheral bloodlymphocytes. Glioma-derived GeneSeq EP399816 Vascular Endothelial GrowthFactor VEGF activity can be determined using Promotion of growth andgrowth factor Accession R08120 assays known in the art, such as thoseproliferation of cells, such disclosed in International Publication No.as vascular endothelial WO0045835, for example. cells. Antagonists maybe useful as anti-angiogenic agents, and may be applicable for cancer.Platelet derived GeneSeq EP682110 Vascular Endothelial Growth FactorVEGF activity can be determined using Promotion of growth and growthfactor Accession R84759 assays known in the art, such as thoseproliferation of cells, such precursor A disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. Platelet derived GeneSeq EP682110 VascularEndothelial Growth Factor VEGF activity can be determined usingPromotion of growth and growth factor Accession R84760 assays known inthe art, such as those proliferation of cells, such precursor Bdisclosed in International Publication No. as vascular endothelialWO0045835, for example. cells. Antagonists may be useful asanti-angiogenic agents, and may be applicable for cancer. Plateletderived GeneSeq EP282317 Vascular Endothelial Growth Factor VEGFactivity can be determined using Promotion of growth and growth factorBvsis Accession P80595 assays known in the art, such as thoseproliferation of cells, such and P80596 disclosed in InternationalPublication No. as vascular endothelial WO0045835, for example. cells.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer. Placental Growth GeneSeq WO9206194 VascularEndothelial Growth Factor VEGF activity can be determined usingPromotion of growth and Factor Accessions assays known in the art, suchas those proliferation of cells, such R23059 and disclosed inInternational Publication No. as vascular endothelial R23060 WO0045835,for example. cells. Antagonists may be useful as anti-angiogenic agents,and may be applicable for cancer. Placental Growth GeneSeq DE19748734Vascular Endothelial Growth Factor VEGF activity can be determined usingPromotion of growth and Factor-2 Accession Y08289 assays known in theart, such as those proliferation of cells, such disclosed inInternational Publication No. as vascular endothelial WO0045835, forexample. cells. Antagonists may be useful as anti-angiogenic agents, andmay be applicable for cancer. Thrombopoietin GeneSeq WO0000612Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative1 Accession Y77244 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietinis involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative2 Accession Y77255 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietinis involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative3 Accession Y77262 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietinis involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative4 Accession Y77267 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietinis involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative5 Accession Y77246 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietinis involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative6 Accession Y77253 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietinis involved in the Thrombopoietin (TPO) can be assayed toThrombocytopenia, cancer. derivative7 Accession Y77256 regulation of thegrowth and differentiation determine regulation of growth and ofmegakaryocytes and preceptors differentiation of megakaryocytes. Molthereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan;29(1): 51-8 and within. Fractalkine GeneSeq U.S. Pat. No. 6,043,086Fractalkine is believed to play a role in Fractalkine activity can bedetermined Immune disorders. Accession Y53255 chemotactic leukocytemigration and using Chemotactic leukocyte migration neurologicaldisorders. assays known in the art, for example: J. Immunol. Methods 33,((1980)); Nature 1997 Jun 5; 387(6633): 611-7. CXC3 GeneSeq WO9757599Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders. Accession secreted proteins involved inbiological using assays known in the art: Methods in W23345 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ. including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-proteincoupled receptors. Over 40 human chemokines have been described, whichbind to ~17 receptors thus far identified. CCR7 GeneSeq U.S. Pat. No.6,153,441 Chemokines are a family of related small, Chemokine activitiescan be determined Soluble CCR7 polypeptides Accession B50859 secretedproteins involved in biological using assays known in the art: Methodsin may be useful for inhibiting processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: chemokine activities andangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, viral infection. Members of this family are involvedin a T. N. C. Wells, and C. A. Power. similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ. including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. NerveGrowth GeneSeq EP414151 Nerve Growth Factor Proliferation assay usingNR6R-3T3 cells Neurological disorders, Factor-beta Accession R11474(Rizzino 1988 Cancer Res. 48: 4266) cancer Nerve Growth GeneSeq EP859056Nerve Growth Factor Proliferation assay using NR6R 3T3 cellsNeurological disorders, Factor-beta2 Accession (Rizzino 1988 Cancer Res.48: 4266 cancer W69725 Neurotrophin-3 GeneSeq WO9821234 Neurotrophinsregulate neuronal cell Trk tyrosine kinase activation assaysNeurological disorders, Accession survival and synaptic plasticity.known in the art can be used to assay for cancer W8889 neurotrophinactivity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6):3555-3560. Neurotrophin-3 GeneSeq WO9325684 Neurotrophins regulateneuronal cell Trk tyrosine kinase activation assays Neurologicaldisorders, Accession R47100 survival and synaptic plasticity. known inthe art can be used to assay for cancer neurotrophin activity, forexample, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560.Neurotrophin-4a GeneSeq WO9325684 Neurotrophins regulate neuronal cellTrk tyrosine kinase activation assays Neurological disorders, AccessionR47101 survival and synaptic plasticity. known in the art can be used toassay for cancer neurotrophin activity, for example, Proc Natl Acad SciUSA 2001 Mar 13; 98(6): 3555-3560. 13; 98(6): 3555-3560 Neurotrophin-4bGeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosinekinase activation assays Neurological disorders, Accession R47102survival and synaptic plasticity. known in the art can be used to assayfor cancer tyrosine kinases. neurotrophin activity, for example, ProcNatl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-4c GeneSeqWO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinaseactivation assays Neurological disorders, Accession R47103 survival andsynaptic plasticity. known in the art can be used to assay for cancertyrosine kinases. neurotrophin activity, for example, Proc Natl Acad SciUSA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-4d GeneSeq WO9325684Neurotrophins regulate neuronal cell Trk tyrosine kinase activationassays Neurological disorders, Accession R47102 survival and synapticplasticity. known in the art can be used to assay for cancer tyrosinekinases. neurotrophin activity, for example, Proc Natl Acad Sci USA 2001Mar 13; 98(6): 3555-3560. Platelet-Derived GeneSeq U.S. Pat. No.5,219,739 Vascular Endothelial Growth Factor VEGF activity can bedetermined using Promotion of growth and Growth Factor Accession R38918assays known in the art, such as those proliferation of cells, such Achain disclosed in International Publication No. as vascular endothelialW00045835, for example. cells. Hematopoietic and immune disorders.Antagonists may be useful as anti-angiogenic agents, and may beapplicable for cancer Platelet-Derived GeneSeq U.S. Pat. No. 5,219,739Vascular Endothelial Growth Factor VEGF activity can be determined usingPromotion of growth and Growth Factor Accession R38919 assays known inthe art, such as those proliferation of cells, such B chain disclosed inInternational Publication No. as vascular endothelial W00045835, forexample. cells. Hematopoietic and immune disorders. Antagonists may beuseful as anti-angiogenic agents, and may be applicable for cancerStromal Derived GeneSeq WO9948528 Stromal Growth Factor Proliferationassay using NR6R-3T3 cells Hematopoietic, immune Factor-1 alphaAccession (Rizzino 1988 Cancer Res. 48: 4266) disorders, cancer Y39995Stromal Derived GeneSeq CA2117953 Stromal Growth Factor Proliferationassay using NR6R-3T3 cells Hematopoietic, immune Factor-1 beta Accession(Rizzino 1988 Cancer Res. 48: 4266) disorders, cancer R75420 TarcGeneSeq WO9711969 Chemotactic for T lymphocytes. May play Chemotacticleukocyte migration assays Antiinflammatory. Immune Accession a role inT-cell development. Thought to are known in the art, for example: J.disorders, cancer W14917 bind CCR8 and CCR4 Immunol. Methods 33 ((1980))Prolactin GeneSeq WO9521625 Prolactin is involved in immune cell Immunecoil proliferation and suppression Reproductive system Accession R78691proliferation and apoptosis. of apoptosis by prolactin can be assayeddisorders, cancer. by methods well-known in the art, for example,Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917: 522-33, andwithin. Prolactin2 GeneSeq U.S. Pat. No. 5,955,346 Prolactin is involvedin immune cell Immune coil proliferation and suppression Reproductivesystem Accession proliferation and apoptosis. of apoptosis by prolactincan be assayed disorders, cancer. Y31764 by methods well-known in theart, for example, Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000;917: 522-33, and within. Follicle stimulating GeneSeq EP974359 FSHstimulates secretion of interleukin-1 FSH activities can be determinedusing Reproductive system hormone Alpha Accession by cells isolated fromwomen in the assays known in the art; J Gend Specif disorders, cancer.subunit Y54160 follicular phase Med 1999 Nov-Dec; 2(6): 30-4; Mol CellEndocrinol. 1997 Nov 15; 134(2): 109-18. Follicle stimulating GeneSeqEP974359 FSH stimulates secretion of interleukin-1 FSH activities can bedetermined using Reproductive system hormone Beta Accession by cellsisolated from women in the assays known in the art; J Gend Specifdisorders, cancer. subunit Y54161 follicular phase Med 1999 Nov-Dec;2(6): 30-4; Mol Cell Endocrinol. 1997 Nov 15; 134(2): 109-18. SubstanceP GeneSeq WO0054053 Substance P is associated with Immuneregulation andbone marrow, cell diabetes mellitus, (tachykinin) Accessionimmunoregulation. proliferation by substance P can be hypertension,cancer B23027 assayed by methods well-known in the art, for example, Laiet al. Proc Natl Acad Sci USA 2001 Mar 27; 98(7): 3970-5; Jallat- Dalozet al. Allergy Asthma Proc 2001 Jan- Feb; 22(1): 17-23; Kahler et al.Exp Lung Res 2001 Jan-Feb; 27(1): 25-46; and Adamus MA and Dabrowski ZJ.J Cell Biochem 2001; 81(3)499-506. Ocytocin GeneSeq WO0053755 Oxytocinis involved in the induction of Oxytocin and prostaglandin E(2) releaseinflammatory disorders (Neurophysin I) Accession prostaglandin (E2)release as well as an and Ocytocin (Ca2+) increase can be immunologicdisorders, B24085 and increased amount of calcium release by assayed bymethods well-known in the art, cancer B24086 smooth muscle cells. forexample, Pavan et al., AM J Obset Gynecol 2000 Jul; 183(1): 76-82 andHolda et al., Cell Calcium 1996 Jul; 20(1): 43 51. Vasopressin GeneSeqWO0053755 Vasopressinis believed to have a direct Vasopressin activitycan be determined inflammatory disorders (Neurophysin II) Accessionantidiuretic action on the kidney, and it is using assays known in theart, for example, immunologic disorders, B24085 and thought to causevasoconstriction of the Endocr Regul 1996 Mar; 30(I): 13-17. cancerB24086 peripheral vessels. IL-1 GeneSeq EP165654 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., in immunologic disorders,P60326 monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis ofneutrophils and T 14-20. lymphocytes, and/or inhibition of interferons.IL-1 mature GeneSeq EP456332 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,Accession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, R14855 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes),Orencole & Dinarclio (1989) Cytokine 1, chemotaxis of neutrophils and T14-20. lymphocytes, and/or inhibition of interferons. IL-1 beta GeneSeqWO9922763 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, Y08322 monocytes, and macrophages.Known Lymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarclio(1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes,and/or inhibition of interferons. IL-3 variants GeneSeq WO8806161Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, P80382, P80383, monocytes, and macrophages. Known Lymphokinesand Interferens: A Practical cancer P80384, and functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press,P80381 of immune cells (e.g., T helper cells, B Washington, D.C. 1987,pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al(1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334.lymphocytes, and/or inhibition of interferons. IL-4 GeneSeq WO8702990Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, P70615 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunolchemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes,and/or inhibition of interferons. IL-4 muteins GeneSeq WO9747744Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, W52151 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer W52152 functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, W52153 of immunecells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; andW52154 cells, eosinophils, and lymphocytes), Siegel & Mostowski (1990) JImmunol W52155 chemotaxis of neutrophils and T Methods 132, 287-295.W52156 lymphocytes, and/or inhibition of W52157 interferons. W52158W52159 W52160 W52161 W52162 W52163 W52164 and W52165 IL-1 alpha GeneSeqEP324447 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, P90108 monocytes, and macrophages.Known Lymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello(1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes,and/or inhibition of interferons. IL-3 variants GeneSeq WO9307171Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R38561, R38562, monocytes, and macrophages. Known Lymphokinesand Interferens: A Practical cancer R38563, R38564, functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press,R38565, R38566, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and R38567, R38568, cells, eosinophils, andlymphocytes), Aarden et al (1987) Eur. J. Immunol 17, R38569, R38570,chemotaxis of neutrophils and T 1411-16. R38571, and lymphocytes, and/orinhibition of R38572 interferons. IL-6 GeneSeq WO9402512 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing inflammatory disorders, Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R45717 and monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer R45718 functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Aarden et al (1987) Eur. J. Immunol 17,chemotaxis of neutrophils and T 1411-16. lymphocytes, and/or inhibitionof interferons. IL-13 GeneSeq WO9404680 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., in immunologic disorders,R48624 monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Boutelier et al (1995) J. Immunol. Methods chemotaxis ofneutrophils and T 181, 29. lymphocytes, and/or inhibition ofinterferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., in immunologic disorders,R47182 monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Siegel & Mostowski (1990) J Immunol chemotaxis ofneutrophils and T Methods 132, 287-295. lymphocytes, and/or inhibitionof interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a groupof multifunctional Interleukin activity can be determined usinginflammatory disorders, Y124X Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R47183 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Siegel & Mostowski (1990) J Immunolchemotaxis of neutrophils and T Methods 132, 287-295. lymphocytes,and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Y124G Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al., inimmunologic disorders, R47184 monocytes, and macrophages. KnownLymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Siegel & Mostowski(1990) J Immunol chemotaxis of neutrophils and T Methods 132, 287-295.lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9317698Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Interleukin-10 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, (precursor) R41664 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes),Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis of neutrophils andT 173, 507-510. lymphocytes, and/or inhibition of interferons. HumanGeneSeq WO9318783-A Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,Interleukin-10 Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., in immunologic disorders, R42642monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis ofneutrophils and T 173, 507-510. lymphocytes, and/or inhibition ofinterferons. Human GeneSeq EP569042 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, interleukin-1 Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, beta precursor. R42447 monocytes, and macrophages. KnownLymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello(1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes,and/or inhibition of interferons. Interleukin- GeneSeq EP578278Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, 1alpha Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al., inimmunologic disorders, R45364 monocytes, and macrophages. KnownLymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophilsand T lymphocytes, and/or inhibition of interferons. Human GeneSeqJP04063595 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, interleukin-3Accession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, variant R22814 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes),Kitamura et al (1989) J Cell Physiol. 140 chemotaxis of neutrophils andT 323-334. lymphocytes, and/or inhibition of interferons. IL-1ifragments GeneSeq EP541920 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,Accession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, R35484 and monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerR35485 functions include stimulating proliferation Approach, Clemens etal., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Orencole & Dinarclio (1989) Cytokine 1, chemotaxis ofneutrophils and T 14-20. lymphocytes, and/or inhibition of interferons.IL-1 inhibitor GeneSeq EPS541920 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, (IL-li) Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R35486 and monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer R35484 functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Orencole & Dinarclio (1989) Cytokine 1,chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition ofinterferons. ICE 22 kD subunit. GeneSeq EP533350 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., in immunologic disorders,R33780 monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225. cells, eosinophils, andlymphocytes), chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. ICE 20 kD subunit. GeneSeq EP533350Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R33781 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells,eosinophils, and lymphocytes), chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. ICE 10 kD GeneSeqEP533350 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, subunitAccession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, R33782 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxisof neutrophils and T lymphocytes, and/or inhibition of interferons.Human GeneSeq WO9317698 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,Interleukin-10 Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., in immunologic disorders, (precursor)R41664 monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Thompson-Snipes et al (1991) J. Exp. Med. chemotaxis ofneutrophils and T 173, 507-510. lymphocytes, and/or inhibition ofinterferons. Human GeneSeq WO9318783 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, Interleukin-10 Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R42642 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Thompson-Snipes et al (1991) J. Exp. Med.chemotaxis of neutrophils and T 173, 507-510. lymphocytes, and/orinhibition of interferons. Human GeneSeq EP569042 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, Interleukin-1 Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, beta precursor R42447 monocytes, and macrophages. KnownLymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Kitamura et al (1989)J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334.lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9403492Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, interleukin-6 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, R49041 monocytes, and macrophages.Known Lymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Aarden et al (1987)Eur. J. Immunol 17, chemotaxis of neutrophils and T 1411-16.lymphocytes, and/or inhibition of interferons. Mutant Interleukin 6GeneSeq WO9411402 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,S176R Accession cytokines synthesized by lymphocytes, assays known inthe art: Matthews et al., in immunologic disorders, R54990 monocytes,and macrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Aardenet al (1987) Eur. J. Immunol 17, chemotaxis of neutrophils and T1411-16. lymphocytes, and/or inhibition of interferons. Interleukin 6GeneSeq JP06145063 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,Accession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, R55256 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Aardenet al (1987) Eur. J. Immunol 17, chemotaxis of neutrophils and T1411-16. lymphocytes, and/or inhibition of interferons. Interleukin 8GeneSeq JP06100595 Interleukins are a group of multifunctionalInterleukin activity can be determined using Soluble IL-8 receptor(IL-8) receptor Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., in polypeptides may be useful R53932monocytes, and macrophages. Known Lymphokines and Interferens: APractical for inhibiting interleukin functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, activities. ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Holmes et al (1991)Science 253, 1278-80. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. 5,328,988Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, interleukin-7 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, R59919 monocytes, and macrophages.Known Lymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Park et al (1990) J.Exp. Med. 171, 1073-79. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. IL-3 containing GeneSeq WO9521254Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, fusion protein. Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, R79342 and monocytes, and macrophages.Known Lymphokines and Interferens: A Practical cancer R79344 functionsinclude stimulating proliferation Approach, Clemens et al., eds, IRLPress, of immune cells (e.g., T helper cells, B Washington, D.C. 1987,pp. 221-225; and cells, eosinophils, and lymphocytes), Kitamura et al(1989) J Cell Physiol. 140 chemotaxis of neutrophils and T 323-334.lymphocytes, and/or inhibition of interferons. IL-3 mutant GeneSeqZA9402636 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, proteinsAccession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, R79254, R79255, monocytes,and macrophages. Known Lymphokines and Interferens: A Practical cancerR79256, R79257, functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, R79258, R79259, of immune cells (e.g., Thelper cells, B Washington, D.C. 1987, pp. 221-225; and R79260, R79261,cells, eosinophils, and lymphocytes), Giri et al (1994) EMBO J. 132822-2830. R79262, R79263, chemotaxis of neutrophils and T R79264,R79265, lymphocytes, and/or inhibition of R79266, R79267, interferons.R79268, R79269, R79270, R79271, R79272, R79273, R79274, R79275, R79276,R79277, R79278, R79279, R79280, R79281, R79282, R79283, R79284, andR79285 IL-12 p40 GeneSeq AU9466072 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, subunit. Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R63018 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells,eosinophils, and lymphocytes), chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. AGF GeneSeq WO9429344Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R64240 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells,eosinophils, and lymphocytes), chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human GeneSeq WO9519786Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, interlaukin-12 40 kD Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, subunit R79187 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Horiet al (1987), Blood 70, 1069-1078. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human GeneSeq WO9530695Interleukins are a group of multifunctional Interleukin activity can bedetermined using Soluble IL-8 receptor interleukin-15 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in polypeptides may be useful receptor from R90843 monocytes,and macrophages. Known Lymphokines and Interferens: A Practical forinhibiting interleukin clone P1 functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, activities. ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Giri et al (1994)EMBO J. 13 2822-2830. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human GeneSeq WO9604306 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing inflammatory disorders, interleukin-7 Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al., inimmunologic disorders, R92796 monocytes, and macrophages. KnownLymphokines and Interferens: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Park et al (1990) J.Exp. Med. 171, 1073-79. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. interleukin-9 GeneSeq WO9604306Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R92797 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Yang et al (1989) Blood 74, 1880-84.chemotaxis of neutrophils and T lymphocytes, and/or inhibition ofinterferons. interleukin-3 GeneSeq WO9604306 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., in immunologic disorders,R92801 monocytes, and macrophages. Known Lymphokines and Interferens: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Kitamura et al (1989) J Cell Physiol. 140 chemotaxis ofneutrophils and T 323-334. lymphocytes, and/or inhibition ofinterferons. Human GeneSeq WO9604306 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, interleukin-5 Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, R92802 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. 140chemotaxis of neutrophils and T 323-334. lymphocytes, and/or inhibitionof interferons. Recombinant GeneSeq DE19617202 Interleukins are a groupof multifunctional Interleukin activity can be determined usinginflammatory disorders, interleukin-16 Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, W33373 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Lim et al (1996) J. Immunol. 156,2566-70. chemotaxis of neutrophils and T lymphocytes, and/or inhibitionof interferons. Human IL-16 GeneSeq DE19617202 Interleukins are a groupof multifunctional Interleukin activity can be determined usinginflammatory disorders, protein Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, W33234 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Lim et al (1996) J. Immunol. 156,2566-70. chemotaxis of neutrophils and T lymphocytes, and/or inhibitionof interferons. Thrl 17 human GeneSeq WO9708321 Interleukins are a groupof multifunctional Interleukin activity can be determined usinginflammatory disorders, interleukin 9 Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, W27521 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells,eosinophils, and lymphocytes), chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Metl 17 human GeneSeqWO9708321 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, interleukin 9Accession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., in immunologic disorders, W27522 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yanget al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human GeneSeq EP86-4585Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, intracellular IL-1 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., in immunologic disorders, receptor W77158 monocytes, andmacrophages. Known Lymphokines and Interferens: A Practical cancerantagonist. functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis ofneutrophils and T 14-20. lymphocytes, and/or inhibition of interferons.Human GeneSeq EP864585 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,interleukin-18 Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., in immunologic disorders, protein(IL-18) W77158 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), USHIO et al (1996) J. Immunol. 156,4274-79. chemotaxis of neutrophils and T lymphocytes, and/or inhibitionof interferons. Human GeneSeq EP861663 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, interleukin-18 Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., in immunologicdisorders, W77077 monocytes, and macrophages. Known Lymphokines andInterferens: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), USHIO et al (1996) J. Immunol. 156,4274-79. chemotaxis of neutrophils and T lymphocytes, and/or inhibitionof interferons. Human interleukin GeneSeq EP861663 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, 18 derivatives Accessions cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., immunologicdisorders, W77083, monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical cancer W77084, functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, W77085, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and W77086, cells, eosinophils, and lymphocytes), Ushio et al(1996) J. Immunol, 156, 4274-79. W77087, chemotaxis of neutrophils and TW77088, and lymphocytes, and/or inhibition of W77089 interferons.Interleukin-9 GeneSeq WO9827997 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, (IL-9) mature Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., immunologicdisorders, protein (Thr117 W68158 monocytes, and macrophages. Known inLymphokines and Interferons: A Practical cancer version). functionsinclude stimulating proliferation Approach, Clemens et al., eds, IRLPress, of immune cells (e.g., T helper cells, B Washington, D.C. 1987,pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al (1989)Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. IL-9 mature GenSeq Accession WO9827997Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, protein variant W68157cytokines synthesized by lymphocytes, assays known in the art: Matthewset al., immunologic disorders, (Met117 version) monocytes, andmacrophages. Known in Lymphokines and Interferons: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yanget al (1989) Blood 74, 1880-84. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeqWO9824904 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, receptorprotein Accession cytokines synthesized by lymphocytes, assays known inthe art: Matthews et al., immunologic disorders, variant #3. W64058monocytes, and macrophages. Known in Lymphokines and Interferons: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis ofneutrophils and T lymphocytes, and/or inhibition of interferons. HumanIL-9 GenSeq Accession WO9824904 Interleukins are a group ofmultifunctional Interleukin activity can be determined using SolubleIL-9 receptor receptor protein W64060 cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., polypeptides maybe useful variant fragment monocytes, and macrophages. Known inLymphokines and Interferons: A Practical for inhibiting interleukinfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, activities. of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Yang et al (1989) Blood 74, 1880-84. chemotaxis ofneutrophils and T lymphocytes, and/or inhibition of interferons. HumanIL-9 GeneSeq WO9824904 Interleukins are a group of multifunctionalInterleukin activity can be determined using Soluble IL-9 receptorreceptor protein Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., polypeptides may be useful variant#3. W64061 monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical for inhibiting interleukin functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press,activities. of immune cells (e.g., T helper cells, B Washington, D.C.1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yang et al(1989) Blood 74, 1880-84. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human GeneSeq WO9817689 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing inflammatory disorders, Interleukin-12 p40 Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,immunologic disorders, protein W51311 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Hori et al (1987),Blood 70, 1069-1078. chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. Human GeneSeq WO9817689 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, Interleukin-12 p35 Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,immunologic disorders, protein W51312 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Hori et al (1987),Blood 70, 1069-1078. chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. Human protein GeneSeq DE19649233-Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, with IL-16 activity Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., immunologic disorders, W63753 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Lim et al (1996) J.Immunol. 156, 2566-70. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human protein GeneSeq DE19649233-Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, with IL-16 activity Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., immunologic disorders, W59425 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Lim et al (1996) J.Immunol. 156, 2566-70. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. 5,747,024Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, interleukin-15 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., immunologic disorders, W53878 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Giri et al (1994)EMBO J. 13 2822-2830. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human wild-type GeneSeq WO9747744Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, interleukin-4 (hIL- Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., immunologic disorders, 4) protein W52149 monocytes, andmacrophages. Known in Lymphokines and Interferons: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Siegel& Mostowski (1990) J Immunol chemotaxis of neutrophils and T Methods132, 287-295. lymphocytes, and/or inhibition of interferons.interleukin-4 GeneSeq WO9747744 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, muteins Accessions cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., immunologicdisorders, W52150, monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical cancer W52151, functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, W52153, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and W52154, cells, eosinophils, and lymphocytes), Siegel &Mostowski (1990) J Immunol W52155, chemotaxis of neutrophils and TMethods 132, 287-295. W52156, lymphocytes, and/or inhibition of W52157,interferons. W52158, W52159, W52160, W52161, W52162, W52163, W52164,W52165, W52166, and W52167 Human interleukin GeneSeq WO9935268Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, 1 delta Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,immunologic disorders, Y28408 monocytes, and macrophages. Known inLymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello(1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes,and/or inhibition of interferons. Human GeneSeq WO9935268 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing inflammatory disorders, interleukin-1 Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,immunologic disorders, receptor Y24395 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer antagonist betafunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes),Orencole & Dinarello (1989) Cytokine 1, chemotaxis of neutrophils and T14-20. lymphocytes, and/or inhibition of interferons. Human EDIRF IIGeneSeq WO9932632 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,protein sequence Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., immunologic disorders, Y22199monocytes, and macrophages. Known in Lymphokines and Interferons: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225. cells, eosinophils, andlymphocytes), chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. Human EDIRF I GeneSeq WO9932632 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing inflammatory disorders, protein sequence Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,immunologic disorders, Y22197 monocytes, and macrophages. Known inLymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophilsand T lymphocytes, and/or inhibition of interferons. Human IL-1RD10GeneSeq WO9919480 Interleukins are a group of multifunctionalInterleukin activity can be determined using Soluble IL-1RD10 receptorprotein sequence Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., polypeptides may be useful Y14131monocytes, and macrophages. Known in Lymphokines and Interferons: APractical for inhibiting interleukin functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, activites. ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Orencole & Dinarello(1989) Cytokine 1, chemotaxis of neutrophils and T 14-20. lymphocytes,and/or inhibition of interferons. Human IL-1RD9 GeneSeq WO9919480Interleukins are a group of multifunctional Interleukin activity can bedetermined using Soluble IL-1RD10 receptor Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,polypeptides may be useful Y14122 monocytes, and macrophages. Known inLymphokines and Interferons: A Practical for inhibiting interleukinfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, activites. of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Orencole & Dinarello (1989) Cytokine 1, chemotaxis ofneutrophils and T 14-20. lymphocytes, and/or inhibition of interferons.Human DNAX GeneSeq WO9919491 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,interleukin-40 Accession cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., immunologic disorders, Y09196monocytes, and macrophages. Known in Lymphokines and Interferons: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225. cells, eosinophils, andlymphocytes), chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. (DIL-40) GeneSeq WO9919491 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, alternative Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., immunologicdisorders, sequence Y09197 monocytes, and macrophages. Known inLymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophilsand T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeqWO9405318 Interleukins are a group of multifunctional Interleukinactivity can be determined using inflammatory disorders, Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., immunologic disorders, R50176 monocytes, and macrophages. Knownin Lymphokines and Interferons: A Practical cancer functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press, ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Lu et al (1994) Jimmunol. Methods 173, chemotaxis of neutrophils and T 19. lymphocytes,and/or inhibition of interferons. Human GeneSeq EP566410 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing inflammatory disorders, adipogenesis Accession cytokinessynthesized by lymphocytes, assays known in the art: Matthews et al.,immunologic disorders, inhibitory factor R43260 monocytes, andmacrophages. Known in Lymphokines and Interferons: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxisof neutrophils and T lymphocytes, and/or inhibition of interferons.IL-11 GeneSeq JP08127539 Interleukins are a group of multifunctionalInterleukin activity can be determined using inflammatory disorders,Accession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., immunologic disorders, W02202 monocytes, andmacrophages. Known in Lymphokines and Interferons: A Practical cancerfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, of immune cells (e.g., T helper cells, B Washington,D.C. 1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Lu etal (1994) J immunol. Methods 173, chemotaxis of neutrophils and T 19.lymphocytes, and/or inhibition of interferons. IL-14 GeneSeq WO9416074Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., immunologicdisorders, R55800 monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Ambrus et al (1993) PNAS 90, 63330-34.chemotaxis of neutrophils and T lymphocytes, and/or inhibition ofinterferons. IL-17 receptor GeneSeq U.S. Pat. No. 6,072,033 Interleukinsare a group of multifunctional Interleukin activity can be determinedusing Soluble IL-17 receptor Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., polypeptides maybe useful B03807 monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical for inhibiting interleukin functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press,activities. of immune cells (e.g., T helper cells, B Washington, D.C.1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Yao et al(1995) J. Immunol. 155, 5483-86. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. IL-17 GeneSeq WO9518826Interleukins are a group of multifunctional Interleukin activity can bedetermined using inflammatory disorders, Accession cytokines synthesizedby lymphocytes, assays known in the art: Matthews et al., immunologicdisorders, R76573 monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical cancer functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Yao et al (1995) J. Immunol. 155,5483-86. chemotaxis of neutrophils and T lymphocytes, and/or inhibitionof interferons. CTLA-8 GeneSeq WO9704097 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., immunologic disorders, W13651monocytes, and macrophages. Known in Lymphokines and Interferons: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225. cells, eosinophils, andlymphocytes), chemotaxis of neutrophils and T lymphocytes, and/orinhibition of interferons. IL-19 GeneSeq WO9808870 Interleukins are agroup of multifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., immunologic disorders, W37935monocytes, and macrophages. Known in Lymphokines and Interferons: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Gallagher et al (2000) Genes Immun. 1, chemotaxis ofneutrophils and T 442-50. lymphocytes, and/or inhibition of interferons.IL-21 (TIF) GeneSeq WO0024758 Interleukins are a group ofmultifunctional Interleukin activity can be determined usinginflammatory disorders, Accession cytokines synthesized by lymphocytes,assays known in the art: Matthews et al., immunologic disorders, Y92879monocytes, and macrophages. Known in Lymphokines and Interferons: APractical cancer functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Parrish-Novak et al (2000) Nature 408, 57-63. chemotaxisof neutrophils and T lymphocytes, and/or inhibition of interferons. IL-8receptor GeneSeq WO9306229 Interleukins are a group of multifunctionalInterleukin activity can be determined using Soluble IL-8 receptorAccession cytokines synthesized by lymphocytes, assays known in the art:Matthews et al., polypeptides may be useful R33420 monocytes, andmacrophages. Known in Lymphokines and Interferons: A Practical forinhibiting interleukin functions include stimulating proliferationApproach, Clemens et al., eds, IRL Press, activities. of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Holmes et al (1991) Science 253,1278-80.. chemotaxis of neutrophils and T lymphocytes, and/or inhibitionof interferons. Human type II GeneSeq U.S. Pat. No. 5,464,937Interleukins are a group of multifunctional Interleukin activity can bedetermined using Soluble type II interleukin-1 interleukin-1 Accessioncytokines synthesized by lymphocytes, assays known in the art: Matthewset al., receptor polypeptides may receptor R85480 monocytes, andmacrophages. Known in Lymphokines and Interferons: A Practical be usefulfor inhibiting functions include stimulating proliferation Approach,Clemens et al., eds, IRL Press, interleukin activities. of immune cells(e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; and cells,eosinophils, and lymphocytes), Orencole & Dinarello (1989) Cytokine 1,chemotaxis of neutrophils and T 14-20. lymphocytes, and/or inhibition ofinterferons. Human GeneSeq EP638644 Interleukins are a group ofmultifunctional Interleukin activity can be determined using SolubleIL-12 receptor interleukin-12 Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., polypeptides maybe useful receptor R69632 monocytes, and macrophages. Known inLymphokines and Interferons: A Practical for inhibiting interleukinfunctions include stimulating proliferation Approach, Clemens et al.,eds, IRL Press, activities. of immune cells (e.g., T helper cells, BWashington, D.C. 1987, pp. 221-225; and cells, eosinophils, andlymphocytes), Hori et al (1987), Blood 70, 1069-1078. chemotaxis ofneutrophils and T lymphocytes, and/or inhibition of interferons.Interleukin 8 GeneSeq U.S. Pat. No. 5,440,021 Interleukins are a groupof multifunctional Interleukin activity can be determined using SolubleIL-8 receptor B receptor B Accession cytokines synthesized bylymphocytes, assays known in the art: Matthews et al., polypeptides maybe useful R80758 monocytes, and macrophages. Known in Lymphokines andInterferons: A Practical for inhibiting interleukin functions includestimulating proliferation Approach, Clemens et al., eds, IRL Press,activities. of immune cells (e.g., T helper cells, B Washington, D.C.1987, pp. 221-225; and cells, eosinophils, and lymphocytes), Holmes etal (1991) Science 253, 1278-80. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human IL-8 GeneSeqJP08103276 Interleukins are a group of multifunctional Interleukinactivity can be determined using Soluble IL-8 receptor A receptorprotein Accession B09989 cytokines synthesized by lymphocytes, assaysknown in the art: Matthews et al., polypeptides may be useful hIL8RAmonocytes, and macrophages. Known in Lymphokines and Interferons: APractical for inhibiting interleukin functions include stimulatingproliferation Approach, Clemens et al., eds, IRL Press, activities. ofimmune cells (e.g., T helper cells, B Washington, D.C. 1987, pp.221-225; and cells, eosinophils, and lymphocytes), Holmes et al (1991)Science 253, 1278-80. chemotaxis of neutrophils and T lymphocytes,and/or inhibition of interferons. Human IL-8 GeneSeq JP08103276Interleukins are a group of multifunctional Interleukin activity can bedetermined Soluble IL-8 receptor receptor protein Accession B09990cytokines synthesized by lymphocytes, using asays known in the art:Matthews et polypeptides may be hIL8R monocytes, and macrophages. Knownal., in Lymphokines and Interferons: A useful for inhibiting functionsinclude stimulating proliferation Practical Approach, Clemens et al.,eds, interleukin activities. of immune cells (e.g., T helper cells, BIRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Holmes et al (1991) Science chemotaxis ofneutrophils and T 253, 1278-80. lymphocytes, and/or inhibition ofinterferons. Interleukin-2 GeneSeq WO9621732- Interleukins are a groupof multifunctional Interleukin activity can be determined Soluble IL-2receptor receptor Accession cytokines synthesized by lymphocytes, usingassays known in the art: Matthews polypeptides may be associated proteinR97569 monocytes, and macrophages. Known et al., in Lymphokines andInterferons: A useful for inhibiting p43 functions include stimulatingproliferation Practical Approach, Clemens et al., eds, interleukinactivities. of immune cells (e.g., T helper cells, B IRL Press,Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Gillis et al (1978) J. chemotaxis of neutrophils and TImmunol. 120, 2027. lymphocytes, and/or inhibition of interferons. HumanGeneSeq WO9629408 Interleukins are a group of multifunctionalInterleukin activity can be determined Soluble IL-17 receptorinterleukin-17 Accession cytokines synthesized by lymphocytes, usingassays known in the art: Matthews polypeptides may be receptor W04185monocytes, and macrophages. Known et al., in Lymphokines andInterferons: A useful for inhibiting functions include stimulatingproliferation Practical Approach, Clemens et al., eds, interleukinactivities. of immune cells (e.g., T helper cells, B IRL Press,Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Yao et al (1995) J. Immunol. chemotaxis of neutrophils andT 155, 5483-86. lymphocytes, and/or inhibition of interferons. HumanGeneSeq WO9619574 Interleukins are a group of multifunctionalInterleukin activity can be determined Soluble IL-11 receptorinterleukin-11 Accession cytokines synthesized by lymphocytes, usingassays known in the art: Matthews polypeptides may be receptor R99090monocytes, and macrophages. Known et al., in Lymphokines andInterferons: A useful for inhibiting functions include stimulatingproliferation Practical Approach, Clemens et al., eds, interleukinactivities. of immune cells (e.g., T helper cells, B IRL Press,Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Lu et al (1994) J immunol. chemotaxis of neutrophils and TMethods 173, 19. lymphocytes, and/or inhibition of interferons. HumanGeneSeq WO9623067 Interleukins are a group of multifunctionalInterleukin activity can be determined Inflammatory disorders,interleukin-1 Accession cytokines synthesized by lymphocytes, usingassays known in the art: Matthews immunologic disorders, receptor W01911monocytes, and macrophages. Known et al., in Lymphokines andInterferons: A cancer accessory protein functions include stimulatingproliferation Practical Approach, Clemens et al., eds, of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Orencole & Dinarello (1989)chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/orinhibition of interferons. AGF Protein GeneSeq U.S. Pat. No. 5,488,032Interleukins are a group of multifunctional Interleukin activity can bedetermined Inflammatory disorders, Accession cytokines synthesized bylymphocytes, using assays known in the art: Matthews immunologicdisorders, R92749 monocytes, and macrophages. Known et al., inLymphokines and Interferons: A cancer functions include stimulatingproliferation Practical Approach, Clemens et al., eds, of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human GeneSeq W09607739Interleukins are a group of multifunctional Interleukin activity can bedetermined Soluble IL-type-3 receptor interleukin-1 type- Accessioncytokines synthesized by lymphocytes, using assays known in the art:Matthews polypeptides may be 3 receptor R91064 monocytes, andmacrophages. Known et al., in Lymphokines and Interferons: A useful forinhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Orencole & Dinarello (1989)chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/orinhibition of interferons. Human GeneSeq WO9720926 Interleukins are agroup of multifunctional Interleukin activity can be determined SolubleIL-13 beta interleukin-13 beta Accession cytokines synthesized bylymphocytes, using assays known in the art: Matthews receptorpolypeptides may receptor W24972 monocytes, and macrophages. Known etal., in Lymphokines and Interferons: A be useful for inhibitingfunctions include stimulating proliferation Practical Approach, Clemenset al., eds, interleukin activities. of immune cells (e.g., T helpercells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Boutelier et al (1995) J. chemotaxis ofneutrophils and T Immunol. Methods 181, 29. lymphocytes, and/orinhibition of interferons. Human GeneSeq WO9720926 Interleukins are agroup of multifunctional Interleukin activity can be determined SolubleIL-13 alpha interleukin-13 Accession cytokines synthesized bylymphocytes, using assays known in the art: Matthews receptorpolypeptides may alpha receptor W24973 monocytes, and macrophages. Knownet al., in Lymphokines and Interferons: A be useful for inhibitingfunctions include stimulating proliferation Practical Approach, Clemenset al., eds, interleukin activities. of immune cells (e.g., T helpercells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Boutelier et al (1995) J. chemotaxis ofneutrophils and T Immunol. Methods 181, 29. lymphocytes, and/orinhibition of interferons. Human GeneSeq U.S. Pat. No. 5,599,905Interleukins are a group of multifunctional Interleukin activity can bedetermined Soluble IL-4 receptor interleukin-4 Accession cytokinessynthesized by lymphocytes, using assays known in the art: Matthewspolypeptides may be receptor W13499 monocytes, and macrophages. Known etal., in Lymphokines and Interferons: A useful for inhibiting functionsinclude stimulating proliferation Practical Approach, Clemens et al.,eds, interleukin activities. of immune cells (e.g., T helper cells, BIRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Siegel & Mostowski (1990) J chemotaxis ofneutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/orinhibition of interferons. Human GeneSeq EP759466 Interleukins are agroup of multifunctional Interleukin activity can be determined SolubleIL-12 beta-2 interleukin-12 Accession cytokines synthesized bylymphocytes, using assays known in the art: Matthews receptorpolypeptides may beta-2 receptor W12771 monocytes, and macrophages.Known et al., in Lymphokines and Interferons: A be useful for inhibitingfunctions include stimulating proliferation Practical Approach, Clemenset al., eds, interleukin activities. of immune cells (e.g., T helpercells, B IRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Hori et al (1987), Blood 70, chemotaxis ofneutrophils and T 1069-1078. lymphocytes, and/or inhibition ofinterferons. Human GeneSeq EP759466 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble IL-12beta-1 interleukin-12 Accession cytokines synthesized by lymphocytes,using assays known in the art: Matthews receptor polypeptides may beta-1receptor. W12772 monocytes, and macrophages. Known et al., inLymphokines and Interferons: A be useful for inhibiting functionsinclude stimulating proliferation Practical Approach, Clemens et al.,eds, interleukin activities. of immune cells (e.g., T helper cells, BIRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Hori et al (1987), Blood 70, chemotaxis ofneutrophils and T 1069-1078. lymphocytes, and/or inhibition ofinterferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble IL-9receptor receptor protein Accessions cytokines synthesized bylymphocytes, using assays known in the art: Matthews polypeptides may beW64055, W64056, monocytes, and macrophages. Known et al., in Lymphokinesand Interferons: A useful for inhibiting and W64057 functions includestimulating proliferation Practical Approach, Clemens et al., eds,interleukin activities. of immune cells (e.g., T helper cells, B IRLPress, Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Yang et al (1989), Blood 74, chemotaxis of neutrophils andT 1880-84.. lymphocytes, and/or inhibition of interferons. IL-10receptor GeneSeq U.S. Pat. No. 5,716,804 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble IL-10receptor Accession cytokines synthesized by lymphocytes, using assaysknown in the art: Matthews polypeptides may be W41804 monocytes, andmacrophages. Known et al., in Lymphokines and Interferons: A useful forinhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities. of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Thompson-Snipes et alchemotaxis of neutrophils and T (1991) J. Exp. Med. 173, 507-510.lymphocytes, and/or inhibition of interferons. Human IL-6 GeneSeqJP11196867 Interleukins are a group of multifunctional Interleukinactivity can be determined Soluble IL-6 receptor receptor AccessionY30938 cytokines synthesized by lymphocytes, using assays known in theart: Matthews polypeptides may be monocytes, and macrophages. Known etal., in Lymphokines and Interferons: A useful for inhibiting functionsinclude stimulating proliferation Practical Approach, Clemens et al.,eds, interleukin activities. of immune cells (e.g., T helper cells, BIRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Aarden et al (1987) Eur. J. chemotaxis ofneutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition ofinterferons. Il-17 receptor GeneSeq U.S. Pat. No. 6,096,305 Interleukinsare a group of multifunctional Interleukin activity can be determinedSoluble IL-17 receptor Accession Y97181 cytokines synthesized bylymphocytes, using assays known in the art: Matthews polypeptides may bemonocytes, and macrophages. Known et al., in Lymphokines andInterferons: A useful for inhibiting functions include stimulatingproliferation Practical Approach, Clemens et al., eds, interleukinactivities. of immune cells (e.g., T helper cells, B IRL Press,Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Yao et al (1995) J. Immunol. chemotaxis of neutrophils andT 155, 5483-86. lymphocytes, and/or inhibition of interferons. Il-17receptor GeneSeq U.S. Pat. No. 6,100,235 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble IL-17receptor Accession Y97131 cytokines synthesized by lymphocytes, usingassays known in the art: Matthews polypeptides may be monocytes, andmacrophages. Known et al., in Lymphokines and Interferons: A useful forinhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities. of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Yao et al (1995) J. Immunol.chemotaxis of neutrophils and T 155, 5483-86. lymphocytes, and/orinhibition of interferons. Human GeneSeq EP509826 Interleukins are agroup of multifunctional Interleukin activity can be determined SolubleIL-3 receptor interleukin-3 Accession cytokines synthesized bylymphocytes, using assays known in the art: Matthews polypeptides may bereceptor R25300 monocytes, and macrophages. Known et al., in Lymphokinesand Interferons: A useful for inhibiting functions include stimulatingproliferation Practical Approach, Clemens et al., eds, interleukinactivities. of immune cells (e.g., T helper cells, B IRL Press,Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Kitamura et al (1989) J Cell chemotaxis of neutrophils andT Physiol. 140 323-334. lymphocytes, and/or inhibition of interferons.Human GM-CSF GeneSeq WO9102063 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble GM-CSFreceptor receptor Accession cytokines synthesized by lymphocytes, usingassays known in the art: Matthews polypeptides may be R10919 monocytes,and macrophages. Known et al., in Lymphokines and Interferons: A usefulfor inhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities. of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. Human IL-5 GeneSeqEP492214 Interleukins are a group of multifunctional Interleukinactivity can be determined Soluble IL-5 receptor receptor alphaAccession cytokines synthesized by lymphocytes, using assays known inthe art: Matthews alpha polypeptides may be chain R25064 monocytes, andmacrophages. Known et al., in Lymphokines and Interferons: A useful forinhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities. of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Kitamura et al (1989) J Cellchemotaxis of neutrophils and T Physiol. 140, 323-334. lymphocytes,and/or inhibition of interferons. Il-5 receptor GeneSeq WO9847923Interleukins are a group of multifunctional Interleukin activity can bedetermined Soluble IL-5 receptor Accession cytokines synthesized bylymphocytes, using assays known in the art: Matthews polypeptides may beW82842 monocytes, and macrophages. Known et al., in Lymphokines andInterferons: A useful for inhibiting functions include stimulatingproliferation Practical Approach, Clemens et al., eds, interleukinactivities. of immune cells (e.g., T helper cells, B IRL Press,Washington, D.C. 1987, pp. cells, eosinophils, and lymphocytes),221-225; and Kitamura et al (1989) J Cell chemotaxis of neutrophils andT Physiol. 140, 323-334. lymphocytes, and/or inhibition of interferons.Il-6 receptor GeneSeq JP05091892 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble IL-6receptor Accession cytokines synthesized by lymphocytes, using assaysknown in the art: Matthews polypeptides may be R37215 monocytes, andmacrophages. Known et al., in Lymphokines and Interferons: A useful forinhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities. of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Aarden et al (1987) Eur. J.chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/orinhibition of interferons. Human B cell GeneSeq AU8928720 Interleukinsare a group of multifunctional Interleukin activity can be determinedSoluble B cell stimulating stimulating factor- Accession P90525cytokines synthesized by lymphocytes, using assays known in the art:Matthews factor-2 receptor 2 receptor monocytes, and macrophages. Knownet al., in Lymphokines and Interferons: A polypeptides may be functionsinclude stimulating proliferation Practical Approach, Clemens et al.,eds, useful for inhibiting of immune cells (e.g., T helper cells, B IRLPress, Washington, D.C. 1987, pp. interleukin activities. cells,eosinophils, and lymphocytes), 221-225. chemotaxis of neutrophils and Tlymphocytes, and/or inhibition of interferons. IL-7 receptor GeneSeqEP403114 Interleukins are a group of multifunctional Interleukinactivity can be determined Soluble IL-7 receptor clone Accessioncytokines synthesized by lymphocytes, using assays known in the art:Matthews polypeptides may be R08330 monocytes, and macrophages. Known etal., in Lymphokines and Interferons: A useful for inhibiting functionsinclude stimulating proliferation Practical Approach, Clemens et al.,eds, interleukin activities. of immune cells (e.g., T helper cells, BIRL Press, Washington, D.C. 1987, pp. cells, eosinophils, andlymphocytes), 221-225; and Park et al (1990) J. Exp. chemotaxis ofneutrophils and T Med. 171, 1073-79. lymphocytes, and/or inhibition ofinterferons. EPO receptor; GeneSeq WO9008822 EPO Receptor is involved inthe EPO Receptor activity can be determined Inflammatory disorders, EPORAccession proliferation and differentiation of using assays known in theart, such as, J immunologic disorders, R06512 erythroblasts. Biol Chem2001 Mar 23; 276(12: 8995-9002; cancer, erythroblast JAK2 proteintyrosine kinase proliferation and activity: Blood 1994 Sep 1; 84(5):1501-7 differentiation and Mol Cell Biol. 1994 Oct; 14(10: 6506-14.IL-15 receptor GeneSeq WO9530695 Interleukins are a group ofmultifunctional Interleukin activity can be determined Soluble IL-15receptor Accession cytokines synthesized by lymphocytes, using assaysknown in the art: Matthews polypeptides may be R90843 monocytes, andmacrophages. Known et al., in Lymphokines and Interferons: A useful forinhibiting functions include stimulating proliferation PracticalApproach, Clemens et al., eds, interleukin activities. of immune cells(e.g., T helper cells, B IRL Press, Washington, D.C. 1987, pp. cells,eosinophils, and lymphocytes), 221-225; and Giri et al (1994) EMBO J. 13chemotaxis of neutrophils and T 2822-2830. lymphocytes, and/orinhibition of interferons. CD137; 4-1BB GeneSeq WO9507984 Activitiesassociated with apoptosis, NF- Apoptosis activity, NF-kB activation, andB Soluble 4-1BB receptor Receptor Protein Accession kB activation, andco-stimulation of and T cell co-stimulation can be polypeptides may beR70977 immune cells such as T and B cells. determined using assays knownin the art: useful for inhibiting Moore et al., 1999, Science,apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation,and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immuneEpsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol.Methods. cells. BCMA GeneSeq WO0068378 Activities associated withapoptosis, NF- Apoptosis activity, NF-kB activation, and B Soluble BCMAreceptor Accession Y71979 kB activation, and co-stimulation of and Tcell co-stimulation can be polypeptides may be immune cells such as Tand B cells. determined using assays known in the art: useful forinhibiting Moore et al., 1999, Science, apoptosis, NF-kB 285(5425):260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad SciUSA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer,1986, J. cells such as B and T Immunol. Methods. cells. CD27 GeneSeqWO9201049 Activities associated with apoptosis, NF- Apoptosis activity,NF-kB activation, and B Soluble CD27 Accession kB activation, andco-stimulation of and T cell co-stimulation can be polypeptides may beR20814 immune cells such as T and B cells. determined using assays knownin the art: useful for inhibiting Moore et al., 1999, Science,apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation,and/or co- Proc Natl Acad Sci USA 94(18): 9792-6; stimulation of immuneEpsevik and Nissen-Meyer, 1986, J. cells such as B and T Immunol.Methods. cells. CD30 GeneSeq DE4200043 Activities associated withapoptosis, NF- Apoptosis activity, NF-kB activation, and B Soluble CD30Accession kB activation, and co-stimulation of and T cell co-stimulationcan be polypeptides may be R35478 immune cells such as T and B cells.determined using assays known in the art: useful for inhibiting Moore etal., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al.,1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6;stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as Band T Immunol. Methods. cells. CD40 GeneSeq WO9945944 Activitiesassociated with apoptosis, Apoptosis activity, NF-kB activation, and BSoluble CD40 Accession NF-kB activation, and co-stimulation of and Tcell co-stimulation can be polypeptides may be Y33499 immune cells suchas T and B cells. determined using assays known in the art: useful forinhibiting Moore et al., 1999, Science apoptosis, NF-kB 285(5425):260-3; Song HY et al., 1997 activation, and/or co- Proc Natl Acad SciUSA 94(18): 9792-6; stimulation of immune Epsevik and Nissen-Meyer,1986, J. cells such as B and T Immunol. Methods. cells. EDAR GenbankActivities associated with apoptosis, Apoptosis activity, NF-kBactivation, and B Immune Disorders, Accession NF-kB activation, andco-stimulation of and T cell co-stimulation can be Lymphomas, X-linkedAAD50077 immune cells such as T and B cells. determined using assaysknown in the art: hypohidrotic ectodermal Moore et al., 1999, Science,dysplasia 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods.OX40; ACT-4 GeneSeq WO9512673 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Immune Disorders, AccessionR74737 NF-kB activation, and co-stimulation of and T cell co-stimulationcan be Lymphomas, T cell immune cells such as T and B cells. determinedusing assays known in the art: disorders Moore et al., 1999, Science,285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18):9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. TACIGeneSeq WO9839361 Activities associated with apoptosis, Apoptosisactivity, NF-kB activation, and B Soluble TACI receptor Accession NF-kBactivation, and co-stimulation of and T cell co-stimulation can bepolypeptides may be W75783 immune cells such as T and B cells.determined using assays known in the art: useful for inhibiting Moore etal., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al.,1997 activation, and/or co- Proc Natl Acad Sci USA 94(18): 9792-6;stimulation of immune Epsevik and Nissen-Meyer, 1986, J. cells such as Band T Immunol. Methods. cells. TNF-R GeneSeq AU9058976 Activitiesassociates with apoptosis, Apoptosis activity, NF-kB activation, and BSoluble TNF-R receptor Accession R10986 NF-kB activation, andco-stimulation of and T cell co-stimulation can be polypeptides may beimmune cells such as T and B cells. determined using assays known in theart: useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc NatlAcad Sci USA 94(18): 9792-6; stimulation of immune Epsevik andNissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells.TNF-RII; TNF GeneSeq EP418014 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Soluble TNFR-II receptor p75receptor; Accession R11141 NF-kB activation, and co-stimulation of and Tcell co-stimulation can be polypeptides may be Death Receptor immunecells such as T and B cells. determined using assays known in the art:useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc NatlAcad Sci USA 94(18)9792-6; stimulation of immune Epsevik andNissen-Meyer, 1986, J. cells such as B and T Immunol. Methods. cells.hAPO-4; TROY GeneSeq WO9911791 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Immune Disorders, AccessionNF-kB activation, and co-stimulation of and T cell co-stimulation can beCancers W93581 immune cells such as T and B cells. determined usingassays known in the art: Moore et al., 1999, Science, 285(5425): 260-3;Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik andNissen-Meyer, 1986, J. Immunol. Methods. TNF-alpha GeneSeq EP205038Activities associated with apoptosis, Apoptosis activity, NF-kBactivation, and B Inflammatory disorders, precursor Accession P60074NF-kB activation, and co-stimulation of and T cell co-stimulation can beimmunologic disorders, immune cells such as T and B cells. determinedusing assays known in the art: cancer Moore et al., 1999, Science,285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18):9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF-GeneSeq EP619372 Activities associated with apoptosis, Apoptosisactivity, NF-kB activation, and B Inflammatory disorders, alphaAccession R62463 NF-kB activation, and co-stimulation of and T cellco-stimulation can be immunologic disorders, immune cells such as T andB cells determined using assays known in the art: cancer Moore et al.,1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad SciUSA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods.Human TNF- GeneSeq EP563714 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Inflammatory disorders,alpha Accession R42679 NF-kB activation, and co-stimulation of and Tcell co-stimulation can be immunologic disorders, immune cells such as Tand B cells. determined using assays known in the art: cancer Moore etal., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc NatlAcad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.Methods. Human TNF- GeneSeq WO0064479 Activities associated withapoptosis, Apoptosis activity, NF-kB activation, and B Inflammatorydisorders, beta (LT-alpha) Accession B37799 NF-kB activation, andco-stimulation of and T cell co-stimulation can be immunologicdisorders, immune cells such as T and B cells. determined using assaysknown in the art: cancer Moore et al., 1999, Science, 285(5425): 260-3;Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik andNissen-Meyer, 1986, J. Immunol. Methods. LT-alpha GeneSeq EP250000Activities associated with apoptosis, Apoptosis activity, NF-kBactivation, and B Inflammatory disorders, Accession P70107 NF-kBactivation, and co-stimulation of and T cell co-stimulation can beimmunologic disorders, immune cells such as T and B cells. determinedusing assays known in the art: cancer Moore et al., 1999, Science,285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18):9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. LT-betaGeneSeq WO9413808 Activities associated with apoptosis, Apoptosisactivity, NF-kB activation, and B Inflammatory disorders, AccessionR56869 NF-kB activation, and co-stimulation of and T cell co-stimulationcan be immunologic disorders, immune cells such as T and B cells.determined using assays known in the art: cancer Moore et al., 1999,Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. OPGLGeneSeq WO9846751 Activities associated with apoptosis, Apoptosisactivity, NF-kB activation, and B Inflammatory disorders, AccessionNF-kB activation, and co-stimulation of and T cell co-stimulation can beimmunologic disorders, W83195 immune cells such as T and B cells.determined using assays known in the art: cancer, loss of bone massMoore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 ProcNatl Acad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J.Immunol. Methods. FasL GeneSeq WO9903999 Activities associated withapoptosis, Apoptosis activity, NF-kB activation, and B Inflammatorydisorders, Accession NF-kB activation, and co-stimulation of and T cellco-stimulation can be immunologic disorders, W98071 immune cells such asT and B cells. determined using assays known in the art: cancer Moore,et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc NatlAcad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.Methods. FasL GeneSeq WO9903998 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Inflammatory disorders,Accession NF-kB activation, and co-stimulation of and T cellco-stimulation can be imunologic disorders, W95041 immune cells such asT and B cells. determined using assays known in the art: cancer Moore etal., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc NatlAcad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.Methods. CD27L GeneSeq WO9405691 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Inflammatory disorders,Accession R50121 NF-kB activation, and co-stimulation of and T cellco-stimulation can be immunologic disorders, immune cells such as T andB cells. determined using assays known in the art: cancer Moore et al.,1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad SciUSA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods.CD30 ligand GeneSeq WO9324135 Activities associated with apoptosis,Apoptosis activity, NF-kB activation, and B Inflammatory disorders,Accession R45007 NF-kB activation, and co-stimulation of and T cellco-stimulation can be immunologic disorders, immune cells such as T andB cells. determined using assays known in the art: cancer Moore et al.,1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad SciUSA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods.CD40L GeneSeq WO9529935 Activities associated with apoptosis, Apoptosisactivity, NF-kB activation, and B Inflammatory disorders, AccessionR85486 NF-kB activation, and co-stimulation of and T cell co-stimulationcan be immunologic disorders, immune cells such as T and B cells.determined using assays known in the art: cancer Moore, et al., 1999,Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods.4-1BB ligand GeneSeq U.S. Pat. No. 5,674,704 Activities associated withapoptosis, Apoptosis activity, NF-kB activation, and B Inflammatorydisorders, Accession NF-kB activation, and co-stimulation of and T cellco-stimulation can be immunologic disorders, W26657 immune cells such asT and B cells. determined using assays known in the art: cancer Moore etal., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc NatlAcad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.Methods. FAS Ligand GeneSeq WO0058465 Activities associated withapoptosis, Apoptosis activity, NF-kB activation, and B Soluble DcR3Inhibitory Accession B19335 NF-kB activation, and co-stimulation of andT cell co-stimulation can be polypeptides may be Protein (DcR3) immunecells such as T and B cells. determined using assays known in the art:useful for inhibiting Moore et al., 1999, Science, apoptosis, NF-kB285(5425): 260-3; Song HY et al., 1997 activation, and/or co- Proc NatlAcad Sci USA 94(18): 9792-6; stimulation of immune Epsevik andNissen-Meyer, 1986, J. cells such as B and T Immunol. Methods cells.OX40L GeneSeq WO9521915 Activities associated with apoptosis, Apoptosisactivity, NF-kB activation, and B Inflammatory disorders, AccessionR79903 NF-kB activation, and co-stimulation of and T cell co-stimulationcan be immunologic disorders, immune cells such as T and B cells.determined using assays known in the art: cancer Moore et al., 1999,Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods.Protease GeneSeq WO9106561 Peptides that inhibit the function/bindingHIV protease activities are known in the art: HIV, inflammatoryinhibitor Accessions of HIV HIV protease assays: EP0387231. Onedisorders, immunologic peptides R12435, R12436, can modify the assay tolook for inhibition disorders, cancer, viral R12437, R12438, using anyof the disclosed protease infections R12439, R12440, inhibitorpolypeptides. and R1244 Retroviral GeneSeq EP387231 Peptides thatinhibit the function/binding HIV protease activities are known in theart: HIV, inflammatory protease Accessions of HIV HIV protease assays:EP0387231. One disorders, immunologic inhibitors R06660, R06661, canmodify the assay to look for inhibition disorders, cancer, viral R06662,R06663, using any of the disclosed protease infections R06664, R06665,inhibitor polypeptides. R06666, R06667, R06668, R06669, R06670, R06671,R06672, R06673, R06674, R06675, and R06676 HIV protease GeneSeqWO9301828 Peptides that inhibit the function/binding HIV proteaseactivities are known in the art: HIV, inflammatory inhibiting Accessionsof HIV HIV protease assays: EP0387231. One disorders, immunologicpeptides R59293, R59294, can modify the assay to look for inhibitiondisorders, cancer, viral R59295, R59296, using any of the disclosedprotease infections R59297, inhibitor polypeptides. R59298, R59299,R592300, R59301, R59302, R59301, R59302, R59303, R59304, R59305, R59306,R59307, R59308, R59309, R59310, R59311, R59312, R59313, R59314, R59315,R59316, R59317 R59318, R59319, R59320, R59321, R59322, R59323, R59324,R59325, R59326, R59327, R59328, R59329, R59330, R59331, R59332, R59333,R59334, R59335, R59336, R59337, R59338, R59339, R59340, R59341, R59342,R59343, R59344, R59345, R59346, R59347, R59348, R59349, and R59350 HIV-1protease GeneSeq DE4412174 Peptides that inhibit the function/bindingHIV protease activities are known in the art: HIV, inflammatoryhinibitors Accessions of HIV HIV protease assays: EP0387231. Onedisorders, immunologic R86326, R86327, can modify the assay to look forinhibition disorders, cancer, viral R86328, R86329, using any of thedisclosed protease infections R86330, R86331, inhibitor polypeptides.R86332, R86333, R86334, R86335, R86336, R86337, R86338, R86339, R86340,R86341, R86342, R86343, R86344, R86345, R86346, R86347, R86348, R86349,R86350, R86351, R86352, R86353, R86354, R86355, R86356, R86357, R86358,R86359, R86360, R86361, R86362, R86363, R86364, R86365, R86366, R86367,R86368, R86369, R86370, and R86371 HIV Inhibitor GeneSeq WO9959615Peptides that inhibit the function/binding HIV protease activities areknown in the art: HIV, inflammatory Peptide Accession of HIV HIVprotease assays: EP0387231. One disorders, immunologic Y89687 can modifythe assay to look for inhibition disorders, cancer, viral using any ofthe disclosed protease infections inhibitor polypeptides. HIV InhibitorGenSeq WO9948513 Peptides that inhibit the function/binding HIV Proteaseactivities are known in the HIV, inflammatory Peptide Accession Y31955of HIV art; HIV protease assays: EP0387231. disorders, immunologic Onecan modify the assay to look for disorders, cancer, viral inhibitionusing any of the disclosed infections. protease inhibitor polypeptides.HIV Inhibitor www.sciencexpress.org; Peptides that inhibit thefunction/binding HIV protease activities are known in the HIV,inflammatory Peptide Published of HIV art: HIV protease assays:EP0387231. disorders, immunologic online 12 Jan. One can modify theassay to look for disorders, cancer, viral 2001; inhibition using any ofthe disclosed infections 10.1126/science.1057453 protease inhibitorpolypeptides. Human monocyte GeneSeq WO9509232 Chemokines are a familyof small, Chemokine activities can be determined Immune disorders,chemoattractant Accession secreted proteins involved in biological usingassays known in the art: Methods in particularly useful for factorhMCP-3 R73915 processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: treating bacterial and/or angiogenesis, and leukocytetrafficking. Chemokine Protocols, Edited by: A. E. I. Proudfoot, viralmenigitis Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to −17receptors thus far identified. Human monocyte GeneSeq WO9509232Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders, chemoattractant Accession secreted proteinsinvolved in biological using assays known in the art: Methods inparticularly useful for factor hMCP-1 R73914 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: treating bacterialand/or angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, viral menigitis Members of this familyare involved in a T. N. C. Wells, and C. A. Power. similarly diverserange of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human gro-beta GeneSeq WO9429341 Chemokines are a family ofsmall, Chemokine activities can be determined Immune disorders,chemokine Accessions secreted proteins involved in biological usingassays known in the art: Methods in inflammatory disorders, R66699 andprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:blood-related disorders, W17671 angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, stem celltransplantation, Members of this family are involved in a T. N. C.Wells, and C. A. Power. cancer similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to —17 receptors thus far identified. Human gro-GeneSeq WO9429341 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, gamma Accessions secretedproteins involved in biological using assays known in the art: Methodsin inflammatory disorders, chemokine R66700 and processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: blood-relateddisorders, W17672 angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, stem cell transplantation,Members of this family are involved in a T. N. C. Wells, and C. A.Power. cancer similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified Human gro-alpha GeneSeq WO9429341Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders, chemokine Accessions secreted proteinsinvolved in biological using assays known in the art: Methods ininflammatory disorders, R66698 and processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: blood-related disorders, W18024angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, stem cell transplantation, Members of this familyare involved in a T. N. C. Wells, and C. A. Power. cancer similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to —17 receptors thus faridentified Human GeneSeq WO9632481 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders,eosinophil- Accession secreted proteins involved in biological usingassays known in the art: Methods in particularly treatment of expressedW05186 processes ranging from hematopoiesis, Molecular Biology, 2000,vol. 138: eosinophilia, inflammation, chemokine (EEC) angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, allergies, asthma, Members of this family are involved in aT. N. C. Wells, and C. A. Power. leukaemia and lymphoma similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified Chemokine-like GeneSeq WO9613587 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer andblood-related protein PF4-414 Accessions secreted proteins involved inbiological using assays known in the art: Methods in disorders,particularly Full-Length and R92318 and processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppressionMature R99809 angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identifiedChemokine-like GeneSeq WO9613587 Chemokines are a family of relatedsmall, Chemokine activities can be determined Cancer and blood-relatedprotein IL-8M3 Accession secreted proteins involved in biological usingassays known in the art: Methods in disorders, particularly R99812processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:myelosuppression angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ; and includinginflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80.rejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified Human GeneSeqWO9613587 Chemokines are a family of related small, Chemokine activitiescan be determined Cancer and blood-related interleukin-8 (IL-8)Accession secreted proteins involved in biological using assays known inthe art: Methods in disorders, particularly R99814 processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppressionangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ; and including inflammation, allergy, tissueHolmes et al (1991) Science 253, 1278-80. rejection, viral infection,and tumor biology. The chemokines exert their effects by acting on afamily of seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified Chemokine-like GeneSeq WO9613587 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer andblood-related protein IL-8M1 Accessions secreted proteins involved inbiological using assays known in the art: Methods in disorders,particularly Full-Length and R99815 and processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppressionMature R99803 angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ; and includinginflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80.rejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identifiedChemokine-like GeneSeq WO9613587 Chemokines are a family of relatedsmall, Chemokine activities can be determined Cancer and blood-relatedprotein IL-8M8 Accessions secreted proteins involved in biological usingassasys known in the art: Methods disorders, particularly Full-Lengthand R99816 and processes ranging from hematopoiesis, in MolecularBiology, 2000, vol. 138: myelosuppression. Mature R99805 angiogenesis,and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ; and including inflammation, allergy, tissue Holmes et al(1991) Science 253, 1278-80. rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Chemokine-like GeneSeq WO9613587 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer andblood-related protein IL-8M8 Accessions secreted proteins involved inbiological using assasys known in the art: Methods in disorders,particularly Full-Length and R99817 and processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression.Mature R99806 angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot; Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ; and includinginflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80.rejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified.Chemokine-like GeneSeq WO9613587 Chemokines are a family of relatedsmall, Chemokine activities can be determined Cancer and blood-relatedprotein IL-8M8 Accessions secreted proteins involved in biological usingassasys known in the art: Methods in disorders, particularly Full-Lengthand R99818 and processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: myelosuppression. Mature R99804 angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ; and including inflammation, allergy, tissue Holmes et al(1991) Science 253, 1278-80. rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Chemokine-like GeneSeq WO9613587 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer andblood-related protein IL-8M8 Accessions secreted proteins involved inbiological using assasys known in the art: Methods in disorders,particularly Full-Length and R99819 and processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: myelosuppression.Mature R99807 angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot; Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified.Chemokine-like GeneSeq WO9613587 Chemokines are a family of relatedsmall, Chemokine activities can be determined Cancer and blood-relatedprotein IL-8M8 Accessions secreted proteins involved in biological usingassasys known in the art: Methods in disorders, particularly Full-Lengthand R99822 and R9807 processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: myelosuppression. Mature angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human foetal GeneSeq WO9622374 Chemokinesare a family of related small, Chemokine activities can be determinedImmune disorders spleen expressed Accession R98499 secreted proteinsinvolved in biological using assasys known in the art: Methods inchemokine, FSEC processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot; Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. Liverexpressed GeneSeq WO9616979 Chemokines are a family of related small,Chemokine activities can be determined Inflammation of the liverchemokine- Accession R95689 secreted proteins involved in biologicalusing assasys known in the art: Methods in 1(LVEC-1) processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Liver expressed GeneSeq WO9616979Chemokines are a family of related small, Chemokine activities can bedetermined Inflammation of the liver chemokine- Accession R95690secreted proteins involved in biological using assasys known in the art:Methods in 2(LVEC-2) processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot; Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Pituitary GeneSeq WO9616979 Chemokines are a family ofrelated small, Chemokine activities can be determined Inflammation,particularly expressed Accession R95691 secreted proteins involved inbiological using assasys known in the art: Methods in of the liverchemokine processes ranging from hematopoiesis, Molecular Biology, 2000,vol. 138: (PGEC) angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot; Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified.Adenoid- GeneSeq WO9617868 Chemokines are a family of related small,Chemokine activities can be determined Inflammation, expressed AccessionR97664 secreted proteins involved in biological using assasys known inthe art: Methods in angiogenesis, chemokine processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: tumorigenesis, (ADEC)angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot; musculoskeletal disorders Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. HumanGeneSeq WO9741230 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, cell chemokineCC-2Accession secreted proteins involved in biological using assays known inthe art: Methods in migration, proliferation, W38170 processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138; anddifferentiation angiogenesis, and leukocyte trafficking. Chemokineprotocols. Edited by: A. E. I. Proudfoot, disorders Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc. Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO9741230 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders, cellchemokine Accession secreted proteins involved in biological usingassays known in the art: Methods in migration, proliferation, HCC-1W38171 processes ranging from hematopiesis, molecular Biology 2000, vol.138: and differentiation anglogenesis and leukocyte trafficking.Chemokine Protocols. Edited by A. E. I. Proudfoot, disorders Members ofthis family are involved in a T. N. C. Wells and C. A. Power similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO9741230 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders, cellchemokine CC-3 Accession secreted proteins involved in biological usingassays known in the art: Methods in migration, proliferation and W38172processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138:differentiation disorders anglogenesis, and leukocyte trafficking.Chemokine Protocols, Edited by A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Novel GeneSeq WO9739126 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune disorders,betachemokine Accession secreted proteins involved in biological usingassays known in the art: Methods in vascular disorders, cancerdesignated PTEC W27271 processes ranging from hemotopoiesis, molecularBiology, 2000, vol. 138: anglogenesis, and leukocyte trafficking.Chemokine Protocols, Edited by A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human CX3C GeneSeq WO9727299 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune disorders,111 amino acid Accession secreted proteins involved in biological usingassays known in the art: Methods in inflammatory diseases, chemokineW23344 processes ranging from hemotopoiesis, molecular Biology, 2000,vol. 138: abnormal proliferation, anglogenesis, and leukocytetrafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot,regeneration, Members of this family are involved in a T. N. C. Wells,and C. A. Power degeneration, and atrophy similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. HumanCCF18 GeneSeq WO9721812 Chemokines are a family of related small,Chemokine activities can be determined Abnormal physiology and chemokineAccession secreted proteins involved in biological using assays known inthe art: Methods in development disorders, W25942 processes ranging fromhemotopoiesis, molecular Biology, 2000, vol. 138: can also be used as ananglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited byA. E. I. Proudfoot, anti-viral agent Members of this family are involvedin a T. N. C. Wells, and C. A. Power similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. Humanbeta- GeneSeq WO9725427 Chemokines are a family of related small,Chemokine activities can be determined Chemotaxis, blood-relatedchemokine Accession secreted proteins involved in biological usingassays known in the art: Methods in disorders, viral infection, H1305(MCP-2) W26655 processes ranging from hemotopoiesis, molecular Biology,2000, vol. 138: HIV, wound healing, anglogenesis, and leukocytetrafficking. Chemokine Protocols, Edited by A. E. I. Proudfoot, cancerMembers of this family are involved in a T. N. C. Wells, and C. A. Powersimilarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO9712914 Chemokines are a family of relatedsmall, Chemokine activities can be determined Inflammatory and immuneeosinocyte CC Accession secreted proteins involved in biological usingassays known in the art: Methods in disorders type chemokine W14990processes ranging from hemotopoiesis, molecular Biology, 2000, vol. 138:eotaxin anglogenesis, and leukocyte trafficking. Chemokine Protocols,Edited by A. E. I. Proudfoot, Members of this family are involved in aT. N. C. Wells, and C. A. Power similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Human thymusGeneSeq WO9711969 Chemokines are a family of related small, Chemokineactivities can be determined Inflammatory and immune and activationAccession secreted proteins involved in biological using assays known inthe art: Methods in disorders regulated W14018 processes ranging fromhemotopoiesis, molecular Biology, 2000, vol. 138: cytokine anglogenesis,and leukocyte trafficking. Chemokine Protocols, Edited by A. E. I.Proudfoot, (TARC) Members of this family are involved in a T. N. C.Wells, and C. A. Power similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq WO9712041 Chemokines are a family of related small, Chemokineactivities can be determined Cancer, would healing, chemokine beta-Accession secreted proteins involved in biological using assays known inthe art: Methods in immune disorders 8 short forms W16315 processesranging from hemotopoiesis, molecular Biology, 2000, vol. 138:anglogenesis, and leukocyte trafficking. Chemokine Protocols, Edited byA. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. MicrophageGeneSeq WO9640923 Chemokines are a family of related small, Chemokineactivities can be determined Inflammatory diseases, derived Accessionsecreted proteins involved in biological using assays known in the art:Methods in wound healin, chemokine, MDC W20058 processes ranging fromhermaatopoiesis, Molecular Biology, 2000, vol. 138: angiogenesisangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq WO9844117 Chemokines are a family of related small, Chemokineactivities can be determined Inflammatory and immune chemokine ZSIG-Accession secreted proteins involved in biological using assays known inthe art: Methods in diseases 35 W30565 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Primate CC GeneSeq WO98328658 Chemokinesare a family of related small, Chemokine activities can be determinedImmune and inflammatory chemokine Accesssion secreted proteins involvedin biological using assays known in the art: Methods in disorders,abnormal “ILINCK” W69990 processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: proliferation, regeneration, angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, generation and atrophy T. N. C. Wells, and C. A. Power.disorders Humana Press Inc., Totowa, NJ Primate CXC GeneSeq WO9832858Chemokines are a family of related small, Chemokine activities can bedetermined Immune and inflammatory chemokine Accession secreted proteinsinvolved in biological using assays known in the art: Methods indisorders, abnormal “IBICK” W69989 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: proliferation, regeneration,angiogenesis, and leukocyte trafficking. Chemokine Protocols. Editd by:A. E. I. Proudfoot, generation and atrophy Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. disorders similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human CC-type GeneSeq WO9831809 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune,inflammatory, chemokine protein Accession secreted proteins involved inbiological using assays known in the art: Methods in and infectiousdisorders, designated SLC W69163 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: cancer (secondary angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, lymphoid Members of this family are involved in a T. N. C.Wells, and C. A. Power. chemokine) similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. HumanCC GeneSeq WO9826071 Chemokines are a family of related small, Chemokineactivities can be determined Cancer and infectious chemokine ELCAccession secreted proteins involved in biological using assays known inthe art: Methods in diseases, particularly protein W62542 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: herpesvirus angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, Members of this family are involved in aT. N. C. Wells, and C. A. Power. similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Human DVic-1GeneSeq Wo9823750 Chemokines are a family of related small, Chemokineactivities can be determined Abnormal proliferation, C-C chemokineAccession secreted proteins involved in biological using assays known inthe art: Methods in regeneration, W60649 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: degeneration, andatrophy angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, disorders, including cancer Members ofthis family are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human C-C GeneSeq WO9823750 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune disorders,cell chemokine Accession secreted proteins involved in biological usingassays known in the art: Methods in proliferation disorders, DGWCCW60650 processes ranging from hematophoiesis, Molecular Biology, 2000,vol. 138: cancer angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identifed. HumanSTCP-1 GeneSeq WO9824907 Chemokines are a family of related small,Chemokine activities can be determined Immune disorders, Accessionsecreted proteins involved in biological using assays known in the art:Methods in particularly T cell related W62783 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: disorders, viralinfection, angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, and inflammation, Members of this familyare involved in a T. N. C. Wells, and C. A. Power. especially jointsimilarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Exodua protein GeneSeq WO9821330 Chamokines are a family ofrelated small, Chemokine activities can be determined Immune andinflammatory Accession secreted proteins involved in biological usingassays known in the art: Methods in disorders, angiogenesis, W61279processes ranging from hematopoiesis, Molecular Biology, 2000, vol.138:cancer, and proliferation angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders,particularly Members of this family are involved in a T. N. C. Wells,and C. A. Power. myeloproliferative similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ diseases includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO9814581 Chemokines are a family of relatedsmall, Chemokine activities can be determined Cancer and degenerativeChr19Kine Acession secreted proteins involved in biological using assaysknown in the art: Methods in disorders protein W50887 processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, andleukocyte trafficking. Chemokine Protocols, Edited by: A. E. I.Proudfoot, Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human T cell GeneSeq U.S. Pat. No.5,780,268 Chemokines are a family of related Chemokine activities can bedetermined Immune, inflammatory, mixed Accession small, secretedproteins involved in using assays known in the art: Mehtods of andinfectious disorders, lymphocyte W58703 biological processes rangingfrom Molecular Biology, 2000, vol. 138: cancer reaction hematopoiesis,angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot,expressed leukocyte trafficking. Members of this T. N. C. Wells, and C.A. Power chemokine family are involved in a similarly diverse HumanaPress Inc., Totowa, NJ (TMEC) range of pathologies includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G- protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human 6CKine GeneSeq W09814581 Chemokines are a family ofrelated Chemokine activities can be determined Cancer and degenerativeprotein Accession small, secreted proteins involved in using assaysknown in the art: Mehtods of disorders W50885 biological processesranging from Molecular Biology, 2000, vol. 138: hematopoiesis,angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot,leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Powerfamily are involved in a similarly diverse Humana Press Inc., Totowa, NJrange of pathologies including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G- protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. human liver and GeneSeq WO9817800Chemokines are a family of related Chemokine activities can bedetermined Immune, inflammatory, activation Accession small, secretedproteins involved in using assays known in the art: Mehtods of andinfectious disorders, regulated W57475 biological processes ranging fromMolecular Biology, 2000, vol. 138: cancer chemokine hematopoiesis,angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot,(LARC) leukocyte trafficking. Members of this T. N. C. Wells, and C. A.Power family are involved in a similarly diverse Humana Press Inc.,Totowa, NJ range of pathologies including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described,which bind to ~17 receptors thus far identified. RANTES GeneSeqWO9744462 Chemokines are a family of related Chemokine activities can bedetermined Infectious diseases, peptide Accession small, secretedproteins involved in using assays known in the art: Mehtods ofparticularly HIV W29538 biological processes ranging from MolecularBiology, 2000, vol. 138: hematopoiesis, angiogenesis, and ChemokineProtocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Membersof this T. N. C. Wells, and C. A. Power family are involved in asimilarly diverse Humana Press Inc., Totowa, NJ range of pathologiesincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G- protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. RANTES 8-68 GeneSeq WO9744462 Chemokines are a family ofrelated Chemokine activities can be determined Infectious diseases,Accession small, secreted proteins involved in using assays known in theart: Mehtods of particularly HIV W29529 biological processes rangingfrom Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, andChemokine Protocols. Edited by: A. E. I. Proudfoot, leukocytetrafficking. Members of this T. N. C. Wells, and C. A. Power family areinvolved in a similarly diverse Humana Press Inc., Totowa, NJ range ofpathologies including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G- protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. RANTES 9-68 GeneSeq WO9744462 Chemokinesare a family of related Chemokine activities can be determinedInfectious diseases, Accession small, secreted proteins involved inusing assays known in the art: Mehtods of particularly HIV W29528biological processes ranging from Molecular Biology, 2000, vol. 138:hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, leukocyte trafficking. Members of this T. N. C. Wells, andC. A. Power family are involved in a similarly diverse Humana PressInc., Totowa, NJ range of pathologies including inflammation, allergy,tissue rejection, viral infection, and tumor biology. The chemokinesexert their effects by acting on a family of seven transmembrane G-protein-coupled receptors. Over 40 human chemokines have been described,which bind to ~17 receptors thus far identified. Human GeneSeq WO9811226Chemokines are a family of related Chemokine activities can bedetermined Abnormal proliferation, chemokine Accession small, secretedproteins involved in using assays known in the art: Mehtods ofregeneration, protein 331D5 W59433 biological processes ranging fromMolecular Biology, 2000, vol. 138: degeneration or atrophy,hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, including cancer leukocyte trafficking. Members of this T.N. C. Wells, and C. A. Power family are involved in a similarly diverseHumana Press Inc., Totowa, NJ range of pathologies includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G- protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO9811226 Chemokines are a family of relatedChemokine activities can be determined Abnormal proliferation, chemokineAccession small, secreted proteins involved in using assays known in theart: Mehtods of regeneration, protein 61164 W59430 biological processesranging from Molecular Biology, 2000, vol. 138: degeneration or atrophy,hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, including cancer leukocyte trafficking. Members of this T.N. C. Wells, and C. A. Power family are involved in a similarly diverseHumana Press Inc., Totowa, NJ range of pathologies includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G- protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Chemokine GeneSeq WO9809171 Chemokines are a family ofrelated Chemokine activities can be determined Immune, Inflammatory,MCP-4 Accession small, secreted proteins involved in using assays knownin the art: Mehtods of and infectious diseases W56690 biologicalprocesses ranging from Molecular Biology, 2000, vol. 138: hematopoiesis,angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot,leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Powerfamily are involved in a similarly diverse Humana Press Inc., Totowa, NJrange of pathologies including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G- protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. Human stromal GeneSeq FR2751658Chemokines are a family of related small, Chemokine activities can bedetermined HIV infections cell-derived Accession secreted proteinsinvolved in biological using assays known in the art: Methods inchemokine, SDF-1 W50766 processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Thymus GeneSeq WO9801557 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune and inflammatoryexpressed Accession W44397 secreted proteins involved in biologicalusing assays known in the art: Methods in disorders chemokine processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: (TECK)angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq WO9801557 Chemokines are a family of related small, Chemokineactivities can be determined Immune and inflammatory chemokine MIP-Accession W44398 secreted proteins involved in biological using assaysknown in the art: Methods in disorders 3alpha processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO9801557 Chemokines are afamily of related small, Chemokine activities can be determined Immuneand inflammatory chemokine MIP- Accession W44399 secreted proteinsinvolved in biological using assays known in the art: Methods indisorders 3beta processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. Humanmonocyte GeneSeq WO9802459 Chemokines are a family of related small,Chemokine activities can be determined Immune disorders, chemotacticAccession W42072 secreted proteins involved in biological using assaysknown in the art: Methods in respiratory disorders, proprotein processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: cancer(MCPP) sequence angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified.Macrophage- GeneSeq U.S. Pat. No. 5,688,927/ Chemokines are a family ofrelated small, Chemokine activities can be determined Immune, andinflammatory derived Accessions U.S. Pat. No. 5,932,703 secretedproteins involved in biological using assays known in the art: Methodsin disorders, cancer chemokine (MDC) W40811 and processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: Y24414 angiogenesis,and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Macrophage GeneSeq U.S. Pat. No.5,932,703 Chemokines are a family of related small, Chemokine activitiescan be determined Immune and inflammatory derived Accession Y24416secreted proteins involved in biological using assays known in the art:Methods in disorders chemokine processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: analogue MDC- angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, eyfy Members of this family are involved in a T. N. C. Wells,and C. A. Power. similarly diverse range of pathologies Humana PressInc., Totowa, NJ including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G-protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No.5,932,703 Chemokines are a family of related small, Chemokine activitiescan be determined Immune and inflammatory derived Accession Y24413secreted proteins involved in biological using assays known in the art:Methods in disorders chemokine processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: analogue MDC angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, (n + 1) Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. MacrophageGeneSeq U.S. Pat. No. 5,932,703 Chemokines are a family of relatedsmall, Chemokine activities can be determined Immune and inflammatoryderived Accession Y24415 secreted proteins involved in biological usingassays known in the art: Methods in disorders chemokine processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: analogueMDC-yl angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, Members of this family are involved in aT. N. C. Wells, and C. A. Power. similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Human typeCC GeneSeq JP11243960 Chemokines are a family of related small,Chemokine activities can be determined Allergic diseases and HIVchemokine Accession Y43178 secreted proteins involved in biologicalusing assays known in the art: Methods in infection eotaxin 3 proteinprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:sequence angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, Members of this family are involved in aT. N. C. Wells, and C. A. Power. similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Human MCP-3GeneSeq WO9946392 Chemokines are a family of related small, Chemokineactivities can be determined Cancer and immune and human Muc-1 AcessionY29893 secreted proteins involved in biological using assays known inthe art: Methods in disorders, particularly HIV core epitope processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: infection(VNT) fusion angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, protein Members of this familyare involved in a T. N. C. Wells, and C. A. Power. similarily diverserange of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human IP-10 and GeneSeq WO9946392 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer and immunehuman Muc-1 Accession Y29894 secreted proteins involved in biologicalusing assays known in the art: Methods in disorders, particularly HIVcore epitope processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: infection (VNT) fusion angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, proteinMembers of this family are involved in a T. N. C. Wells, and C. A.Power. similarily diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human IP-10 and GeneSeq W09946392Chemokines are a family of related small, Chemokine activities can bedetermined Cancer and immune HIV-1 gp 120 Accession Y29897 secretedproteins involved in biological using assays known in the art: Methodsin disorders, particularly HIV hypervariable processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: infection regionfusion angiogenesis, and leukocyte trafficking. Chemokine Protocols.Edited by: A. E. I. Proudfoot, protein Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarily diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. Humanmammary GeneSeq WO9936540 Chemokines are a family of related small,Chemokine activities can be determined Breast disease, includingassociated Accessions secreted proteins involved in biological usingassays known in the art: Methods in cancer chemokine Y29092 andprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:(MACK) protein Y29093 angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Full-Length and Members ofthis family are involved in a T. N. C. Wells, and C. A. Power. Maturesimilarily diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Tim-1 protein GeneSeq WO9933990 Chemokines are a family ofrelated small, Chemokine activities can be determined Inflammation dueto stimuli Accession secreted proteins involved in biological usingassays known in the art: Methods in such as heart attacks and Y28290processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:stroke, infection, physical angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, trauma, UV orionizing Members of this family are involved in a T. N. C. Wells, and C.A. Power. radiation, burns, frostbite similarily diverse range ofpathologies Humana Press Inc., Totowa, NJ or corrosive chemicalsincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human Lkn-1 Full- GeneSeq WO9928473 Chemokines are a familyof related small, Chemokine activities can be determined HIV infectionand cancer, Length and Accessions and secreted proteins involved inbiological using assays known in the art: Methods in particularlyleukemia Mature protein Y17280, Y17274, WO9928472 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: Y17281, andangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Y17275 Members of this family are involved in a T.N. C. Wells, and C. A. Power. similarily diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. N-terminalGeneSeq WO9920759 Chemokines are a family of related small, Chemokineactivities can be determined Inhibit or stimulate modified AccessionY05818 secreted proteins involved in biological using assays known inthe art: Methods in angiogenesis, inhibit the chemokine met- processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: bindingof HIV hSDF-1 alpha angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarily diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified.N-terminal GeneSeq WO9920759 Chemokines are a family of related small,Chemokine activities can be determined Inhibit or stimulate modifiedAccession Y05819 secreted proteins involved in biological using assaysknown in the art: Methods in angiogenesis, inhibit the chemokine met-processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:binding of HIV, hSDF-1 beta angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, antiinflammatory;Members of this family are involved in a T. N. C. Wells, and C. A.Power. immunosuppressant similarily diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. N-terminalGeneSeq WO9920759 Chemokines are a family of related small, Chemokineactivities can be determined Inhibit or stimulate modified AccessionY05820 secreted proteins involved in biological using assays known inthe art: Methods in angiogenesis, inhibit the chemokine processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: bindingof HIV, GroHEK/hSDF- angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, antiinflammatory; 1alphaMembers of this family are involved in a T. N. C. Wells, and C. A.Power. immunosuppressant similarily diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. N-terminalGeneSeq WO9920759 Chemokines are a family of related small, Chemokineactivities can be determined Inhibit or stimulate modified AccessionY05821 secreted proteins involved in biological using assays known inthe art: Methods in angiogenesis, inhibit the chemokine processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: bindingof HIV, GroHEK/hSDF- angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, antiinflammatory; 1beta.Members of this family are involved in a T. N. C. Wells, and C. A.Power. immunosuppressant similarily diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. ChemokineGeneSeq WO9912968 Chemokines are a family of related small, Chemokineactivities can be determined Increase or enhance an Eotaxin Accessionsecreted proteins involved in biological using assays known in the art:Methods in inflammatory response, an Y14230 processes ranging fromhematopoiesis, Molecular Bilogy, 2000, vol. 138: immune responseagiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, orhaematopoietic cell- Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. associated activity;treat a similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ vascular indication; including inflammation, allergy, tissueCancer; enhance wound rejection, viralk infection, and tumor healing, toprevent or treat biology. The chemokines exert their asthma, organtransplant effects by acting on a family of seven rejction, rheumatoidtransmembrane G-protein-coupled arthritis or allergy receptors. Over 40human chemokines have been described, which bind to ~17 receptors thusfar identified. Chemokine GeneSeq WO9912968 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune disorders,hMCP1a Accession secreted proteins involved in biological using assaysknown in the art: Methods in Vascular disorders, Y14225 processesranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Woundhealing, cancer, agiogenesis, and leukocye trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, prevent organ transplantMembers of this family are involved in a T. N. C. Wells, and C. A.Power. rejection, Increase or similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ enhance an inflammatory includinginflammation, allergy, tissue response, rejection, viralk infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Chemokine GeneSeq WO9912968 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune disorders,hMCP1b Accession secreted proteins involved in biological using assaysknown in the art: Methods in Vascular disorders, Y14226 processesranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Woundhealing, cancer, agiogenesis, and leukocye trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, prevent organ transplantMembers of this family are involved in a T. N. C. Wells, and C. A.Power. rejection, Increase or similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ enhance an inflammatory includinginflammation, allergy, tissue response, rejection, viralk infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Chemokine GeneSeq WO9912968 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune disorders,hSDF1b Accession secreted proteins involved in biological using assaysknown in the art: Methods in Vascular disorders, Y14228 processesranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Woundhealing, cancer, agiogenesis, and leukocye trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, prevent organ transplantMembers of this family are involved in a T. N. C. Wells, and C. A.Power. rejection, Increase or similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ enhance an inflammatory includinginflammation, allergy, tissue response, rejection, viralk infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Chemokine GeneSeq WO9912968 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune disorders,hIL-8 Accession secreted proteins involved in biological using assaysknown in the art: Methods in Vascular disorders, Y14229 processesranging from hematopoiesis, Molecular Bilogy, 2000, vol. 138: Woundhealing, cancer, agiogenesis, and leukocye trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, prevent organ transplantMembers of this family are involved in a T. N. C. Wells, and C. A.Power. rejection, Increase or similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ; and enhance an inflammatory includinginflammation, allergy, tissue Holmes et al (1991) Science 253, 1278-80.response, rejection, viralk infection, and tumor biology. The chemokinesexert their effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. ChemokineGeneSeq WO9912968 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, hMCP1 Accession secretedproteins involved in biological using assays known in the art: Methodsin Vascular disorders, Y14222 processes ranging from hematopoiesis,Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis,and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, prevent organ transplant Members of this family are involvedin a T. N. C. Wells, and C. A. Power. rejection, Increase or similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ enhance aninflammatory including inflammation, allergy, tissue response,rejection, viralk infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. ChemokineGeneSeq WO9912968 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, hMCP2 Accession secretedproteins involved in biological using assays known in the art: Methodsin Vascular disorders, Y14223 processes ranging from hematopoiesis,Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis,and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, prevent organ transplant Members of this family are involvedin a T. N. C. Wells, and C. A. Power. rejection, Increase or similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ enhance aninflammatory including inflammation, allergy, tissue response,rejection, viralk infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. ChemokineGeneSeq WO9912968 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, hMCP3 Accession secretedproteins involved in biological using assays known in the art: Methodsin Vascular disorders, Y14224 processes ranging from hematopoiesis,Molecular Bilogy, 2000, vol. 138: Wound healing, cancer, agiogenesis,and leukocye trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, prevent organ transplant Members of this family are involvedin a T. N. C. Wells, and C. A. Power. rejection, Increase or similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ enhance aninflammatory including inflammation, allergy, tissue response,rejection, viralk infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. C-Cchemokine, GeneSeq EP905240 Chemokines are a family of related small,Chemokine activities can be determined Inflammatory, Immune and MCP2Accession secreted proteins involved in biological using assays known inthe art: Methods in infectious diseases; Y05300 processes ranging fromhematopoiesis, Molecular Bilogy, 2000, vol. 138: pulmonary diseases andagiogenesis, and leukocye trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, skin disorders; tumours, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. and angiogenesis-andsimilarly diverse range of pathologies Humana Press Inc., Totowa, NJhaematopoiesis-related including inflammation, allergy, tissue diseasesrejection, viralk infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Wild typeGeneSeq EP906954 Chemokines are a family of related small, Chemokineactivities can be determined Inflammatory, Immune and monocyte Accessionsecreted proteins involved in biological using assays known in the art:Methods in infectious diseases; chemotactic Y07233 processes rangingfrom hematopoiesis, Molecular Bilogy, 2000, vol. 138: pulmonary diseasesand protein 2 agiogenesis, and leukocye trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, skin disorders; tumours,Members of this family are involved in a T. N. C. Wells, and C. A.Power. and angiogenesis-and similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ haematopoiesis-related includinginflammation, allergy, tissue diseases rejection, viralk infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Truncated GeneSeq EP906954 Chemokines are a family ofrelated small, Chemokines activities can be determined Inflammatory,immune and monocyte Accession secreted proteins involved in biologicalusing assays known in the art: Methods in infectious diseases;chemotactic Y07234 processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: pulmonry diseases and skin protein 2 (6-76)angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, disorders; tumours, and Members of this family areinvolved in a T. N. C. Wells, and C. A. Power, angiogenesis-andsimilarly diverse range of pathologies Humana Press Inc., Totowa, NJhaematopoiesis-related including inflammation, allergy, tissue diseasesrejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a fmaily of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. TruncatedGeneSeq EP905241; Chemokines are a family of related small, Chemokinesactivities can be determined Inflammatory, immune and RANTES AccessionsEP906954 secreted proteins involved in biological using assays known inthe art: Methods in infectious diseases; protein (3-68) Y07236 andprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:pulmonry diseases and skin Y07232 angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot,disorders; tumours, and Members of this family are involved in a T. N.C. Wells, and C. A. Power, angiogenesis-and similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ haematopoiesis-relatedincluding inflammation, allergy, tissue diseases rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a fmaily of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Wild type GeneSeq EP905241 Chemokines area family of related small, Chemokines activities can be determinedInflammatory, immune and monocyte Accession secreted proteins involvedin biological using assays known in the art: Methods in infectiousdiseases; chemotactic Y07237 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: pulmonry diseases and skin protein 2angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, disorders; tumours, and Members of this family areinvolved in a T. N. C. Wells, and C. A. Power, angiogenesis-andsimilarly diverse range of pathologies Humana Press Inc., Totowa, NJhaematopoiesis-related including inflammation, allergy, tissue diseasesrejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a fmaily of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. TruncatedGeneSeq EP905241 Chemokines are a family of related small, Chemokinesactivities can be determined Inflammatory, immune and monocyte Accessionsecreted proteins involved in biological using assays known in the art:Methods in infectious diseases; chemotactic Y07238 processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: pulmonry diseasesand skin protein 2 (6-76) angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders; tumours,and Members of this family are involved in a T. N. C. Wells, and C. A.Power, angiogenesis-and similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ haematopoiesis-related including inflammation,allergy, tissue diseases rejection, viral infection, and tumor biology.The chemokines exert their effects by acting on a fmaily of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. Apartial GeneSeq EP897980 Chemokines are a family of related small,Chemokines activities can be determined Soluble CXCR4B receptor CXCR4BAccession secreted proteins involved in biological using assays known inthe art: Methods in polypeptides may be useful protein W97363 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: forinhibiting chemokine angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, activities and viralinfection. Members of this family are involved in a T. N. C. Wells, andC. A. Power, similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a fmaily of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Interferon GeneSeq U.S. Pat. No.5,871,723 Chemokines are a family of related small, Chemokinesactivities can be determined Angiogenesis, Cancer, gamma- Accessionsecreted proteins involved in biological using assays known in the art:Methods in Inflammatory and Immune inducible W96709 processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: disorders,Cardio-Vascular protein (IP-10) angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, discorders,Musco-skeletal Members of this family are involved in a T. N. C. Wells,and C. A. Power, disorders similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a fmaily of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. A monokineGeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of relatedsmall, Chemokines activities can be determined Angiogenesis, Cancer,induced by Accession secreted proteins involved in biological usingassays known in the art: Methods in Inflammatory and Immune gamma-W96710 processes ranging from hematopoiesis, Molecular Biology, 2000,vol. 138: disorders, Cardio-Vascular interferon angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, discorders, Musco-skeletal (MIG) Members of this family areinvolved in a T. N. C. Wells, and C. A. Power, disorders similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a fmaily ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Interleukin-8 GeneSeq U.S. Pat. No. 5,871,723 Chemokines area family of related small, Chemokines activities can be determinedAngiogenesis, Cancer, (IL-8) protein. Accession secreted proteinsinvolved in biological using assays known in the art: Methods inInflammatory and Immune W96711 processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: disorders, Cardio-Vascularangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, discorders, Musco-skeletal Members of this familyare involved in a T. N. C. Wells, and C. A. Power, disorders similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ; andincluding inflammation, allergy, tissue Holmes et al (1991) Science 253,1278-80. rejection, viral infection, and tumor biology. The chemokinesexert their effects by acting on a fmaily of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. EpithelialGeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of relatedsmall, Chemokines activities can be determined Angiogenesis, Cancer,neutrophil Accession secreted proteins involved in biological usingassays known in the art: Methods in Inflammatory and Immune activatingW96712 processes ranging from hematopoiesis, Molecular Biology, 2000,vol. 138: disorders, Cardio-Vascular protein-78 angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, discorders, Musco-skeletal (ENA-78) Members of this familyare involved in a T. N. C. Wells, and C. A. Power, disorders similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a fmaily ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Growth related GeneSeq U.S. Pat. No. 5,871,723 Chemokinesare a family of related small, Chemokines activities can be determinedAngiogenesis, Cancer, oncogene-alpha Accession secreted proteinsinvolved in biological using assays known in the art: Methods inInflammatory and Immune (GRO-alpha). W96713 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: disorders,Cardio-Vascular angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, discorders, Musco-skeletalMembers of this family are involved in a T. N. C. Wells, and C. A.Power, disorders similarly diverse range of pathologies Humana PressInc., Totowa, NJ including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a fmaily of seven transmembrane G-protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. Growth related GeneSeq U.S. Pat. No.5,871,723 Chemokines are a family of related small, Chemokine activitiescan be determined Angiogenesis, Cancer, oncogene-beta Accession secretedproteins involved in biological using assays known in the art: Methodsin Inflammatory and Immune (GRO-beta). W96714 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: disorders,Cardio-Vascular angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletalMembers of this family are involved in a T. N. C. Wells, and C. A.Power, disorders similarly diverse range of pathologies Humana PressInc., Totowa, NJ including inflammation, allergy, tissue rejection,viral infection and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified Growth related GeneSeq U.S. Pat. No.5,871,723 Chemokines are a family of related small, Chemokine activitiescan be determined Angiogenesis, Cancer, oncogene-gamma Accession W96715secreted proteins involved in biological using assays known in the art:Methods in Inflammatory and Immune (GRO-gamma) processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: disorders,Cardio-Vascular angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletalMembers of this family are involved in a T. N. C. Wells, and C. A.Power, disorders similarly diverse range of pathologies Humana PressInc., Totowa, NJ including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G-protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. A platelet basic GeneSeq U.S. Pat.No. 5,871,723 Chemokines are a family of related small, Chemokineactivities can be determined Angiogenesis, Cancer, protein (PBP)Accession W96716 secreted proteins involved in biological using assaysknown in the art: Methods in Inflammatory and Immune processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: disorders,Cardio-Vascular angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, disorders, Musco-skeletalMembers of this family are involved in a T. N. C. Wells, and C. A.Power, disorders similarly diverse range of pathologies Humana PressInc., Totowa, NJ including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G-protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. Connective tissue GeneSeqAccessionU.S. Pat. No. 5,871,723 Chemokines are a family of related small,Chemokine activities can be determined Angiogenesis, Cancer, activatingprotein- S96717 secreted proteins involved in biological using assaysknown in the art: Methods in Inflammatory and Immune III (CTAP-III)processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:disorders, Cardio-Vascular angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, disorders,Musco-skeletal Members of this family are involved in a T. N. C. Wells,and C. A. Power, disorders similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Beta-GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family of relatedsmall, Chemokine activities can be determined Angiogenesis, Cancer,thromboglobulin Accession W96718 secreted proteins involved inbiological using assays known in the art: Methods in Inflammatory andImmune protein (beta-TG) processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, disorders, Musco-skeletal Members of this family are involvedin a T. N. C. Wells, and C. A. Power, disorders similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified.Neutrophil GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family ofrelated small, Chemokine activities can be determined Angiogenesis,Cancer, activating peptide- Accession W96719 secreted proteins involvedin biological using assays known in the art: Methods in Inflammatory andImmune 2 (NAP-2) processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, disorders, Musco-skeletal Members of this family are involvedin a T. N. C. Wells, and C. A. Power, disorders similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified.Granulocyte GeneSeq U.S. Pat. No. 5,871,723 Chemokines are a family ofrelated small, Chemokine activities can be determined Angiogenesis,Cancer, chemotactic Accession W96720 secreted proteins involved inbiological using assays known in the art: Methods in Inflammatory andImmune protein-2 (GCP-2) processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: disorders, Cardio-Vascular angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, disorders, Musco-skeletal Members of this family are involvedin a T. N. C. Wells, and C. A. Power, disorders similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. HumanGeneSeq EP887409 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, viral, chemokine MIG-Accession W90124 secreted proteins involved in biological using assaysknown in the art: Methods in parasitic, fungal or beta protein processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138: bacterialinfections, angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Cancer; autoimmune Members ofthis family are involved in a T. N. C. Wells, and C. A. Power, diseasesor transplant similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ rejection including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G-protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. Human ZCHEMO-8 GeneSeq WO9854326Chemokines are a family of related small, Chemokine activities can bedetermined Immune disorders, cancer, Accession W82716 secreted proteinsinvolved in biological using assays known in the art: Methods inmyelopoietic disorders, processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: autoimmune disorders and angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, immunodeficiencies, Members of this family are involved in aT. N. C. Wells, and C. A. Power, Inflammatory and similarly diverserange of pathologies Humana Press Inc., Totowa, NJ infectious diseases,including inflammation, allergy, tissue Vascular disorders, woundrejection, viral infection, and tumor healing biology. The chemokinesexert their effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Human Act-2GeneSeq WO9854326 Chemokines are a family of related small, Chemokineactivities can be determined Immune disorders, cancer, protein AccessionW82717 secreted proteins involved in biological using assays known inthe art: Methods in myelopoietic disorders, processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: autoimmune disordersand angiogenesis, and leukocyte trafficking. Chemokine Protocols. Editedby: A. E. I. Proudfoot, immunodeficiencies, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power, Inflammatory andsimilarly diverse range of pathologies Humana Press Inc., Totowa, NJinfectious diseases, including inflammation, allergy, tissue Vasculardisorders, wound rejection, viral infection, and tumor healing biology.The chemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. HumanSISD GeneSeq WO9854326 Chemokines are a family of related small,Chemokine activities can be determined Immune disorders, cancer, proteinAcession secreted proteins involved in biological using assays known inthe art: Methods in myelopoietic disorders, W82720 processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: autoimmunedisorders and angiogenesis, and leukocyte trafficking. ChemokineProtocols, Edited by: A. E. I. Proudfoot, immunodeficiencies, Members ofthis family are involved in a T. N. C. Wells, and C. A. Power.Inflammatory and similarly diverse range of pathologies Humana PressInc., Totowa, NJ infectious diseases, including inflammation, allergy,tissue Vascular disorders, wound rejection, viral infection, and tumorhealing biology. The chemokines exert their effects by acting on afamily of seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human M110 GeneSeq WO9854326 Chemokines are a family ofrelated Chemokine activities can be determined Immune disorders, cancer,protein Accession small, secreted proteins involved in using assaysknown in the art: Mehtods of myelopoietic disorders, W82721 biologicalprocesses ranging from Molecular Biology, 2000, vol. 138: autoimmunedisorders and hematopoiesis, angiogenesis, and Chemokine Protocols.Edited by: A. E. I. Proudfoot, immunodeficiencies, leukocytetrafficking. Members of this T. N. C. Wells, and C. A. PowerInflammatory and family are involved in a similarly diverse Humana PressInc., Totowa, NJ infectious diseases, range of pathologies includingVascular disorders, wound inflammation, allergy, tissue rejection,healing viral infection, and tumor biology. The chemokines exert theireffects by acting on a family of seven transmembrane G- protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. Human M11A GeneSeq W09854326Chemokines are a family of related Chemokine activities can bedetermined Immune disorders, cancer, protein Accession small, secretedproteins involved in using assays known in the art: Mehtods ofmyelopoietic disorders, W82722 biological processes ranging fromMolecular Biology, 2000, vol. 138: autoimmune disorders andhematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, immunodeficiencies, leukocyte trafficking. Members of thisT. N. C. Wells, and C. A. Power Inflammatory and family are involved ina similarly diverse Humana Press Inc., Totowa, NJ infectious diseases,range of pathologies including Vascular disorders, wound inflammation,allergy, tissue rejection, healing viral infection, and tumor biology.The chemokines exert their effects by acting on a family of seventransmembrane G- protein-coupled receptors. Over 40 human chemokineshave been described, which bind to ~17 receptors thus far identified.Human CCC3 GeneSeq WO9854326 Chemokines are a family of relatedChemokine activities can be determined Immune disorders, cancer, proteinAccession small, secreted proteins involved in using assays known in theart: Mehtods of myelopoietic disorders, W82723 biological processesranging from Molecular Biology, 2000, vol. 138: autoimmune disorders andhematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, immunodeficiencies, leukocyte trafficking. Members of thisT. N. C. Wells, and C. A. Power Inflammatory and family are involved ina similarly diverse Humana Press Inc., Totowa, NJ infectious diseases,range of pathologies including Vascular disorders, wound inflammation,allergy, tissue rejection, healing viral infection, and tumor biology.The chemokines exert their effects by acting on a family of seventransmembrane G- protein-coupled receptors. Over 40 human chemokineshave been described, which bind to ~17 receptors thus far identified. Ahuman L105 GeneSeq WO9856818 Chemokines are a family of relatedChemokine activities can be determined Cancer, wound healing chemokineAccession small, secreted proteins involved in using assays known in theart: Mehtods of designated W87588 biological processes ranging fromMolecular Biology, 2000, vol. 138: huL105_3. hematopoiesis,angiogenesis, and Chemokine Protocols. Edited by: A. E. I. Proudfoot,leukocyte trafficking. Members of this T. N. C. Wells, and C. A. Powerfamily are involved in a similarly diverse Humana Press Inc., Totowa, NJrange of pathologies including inflammation, allergy, tissue rejection,viral infection, and tumor biology. The chemokines exert their effectsby acting on a family of seven transmembrane G- protein-coupledreceptors. Over 40 human chemokines have been described, which bind to~17 receptors thus far identified. A human L105 GeneSeq WO9856818Chemokines are a family of related Chemokine activities can bedetermined Cancer, wound healing chemokine Accession small, secretedproteins involved in using assays known in the art: Mehtods ofdesignated W87589 biological processes ranging from Molecular Biology,2000, vol. 138: huL105_7. hematopoiesis, angiogenesis, and ChemokineProtocols. Edited by: A. E. I. Proudfoot, leukocyte trafficking. Membersof this T. N. C. Wells, and C. A. Power family are involved in asimilarly diverse Humana Press Inc., Totowa, NJ range of pathologiesincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G- protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human mature GeneSeq WO9848828 Chemokines are a family ofrelated Chemokine activities can be determined Infectious diseases,sepsis gro-alpha Accession small, secreted proteins involved in usingassays known in the art: Mehtods of polypeptide W81498 biologicalprocesses ranging from Molecular Biology, 2000, vol. 138: used to treathematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, sepsis leukocyte trafficking. Members of this T. N. C.Wells, and C. A. Power family are involved in a similarly diverse HumanaPress Inc., Totowa, NJ range of pathologies including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G- protein-coupled receptors. Over 40 human chemokineshave been described, which bind to ~17 receptors thus far identified.Human mature GeneSeq WO9848828 Chemokines are a family of relatedChemokine activities can be determined Infectious diseases, sepsisgro-gamma Accession small, secreted proteins involved in using assaysknown in the art: Mehtods of polypeptide W81500 biological processesranging from Molecular Biology, 2000, vol. 138: used to treathematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E.I. Proudfoot, sepsis leukocyte trafficking. Members of this T. N. C.Wells, and C. A. Power family are involved in a similarly diverse HumanaPress Inc., Totowa, NJ range of pathologies including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G- protein-coupled receptors. Over 40 human chemokineshave been described, which bind to ~17 receptors thus far identified.Human thymus GeneSeq WO0053635 Chemokines are a family of relatedChemokine activities can be determined Inflammatory disorders, expressedAccessions small, secreted proteins involved in using assays known inthe art: Mehtods of cancer, Immune and chemokine B19607 and biologicalprocesses ranging from Molecular Biology, 2000, vol. 138: vasculardisorders TECK and B19608 hematopoiesis, angiogenesis, and ChemokineProtocols. Edited by: A. E. I. Proudfoot, TECK variant leukocytetrafficking. Members of this T. N. C. Wells, and C. A. Power family areinvolved in a similarly diverse Humana Press Inc., Totowa, NJ range ofpathologies including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G- protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related Chemokine activities can be determined Autoimmunedisorders, chemokine Accession B15791 small, secreted proteins involvedin using assays known in the art: Mehtods of Immune, Vascular andSDF1alpha biological processes ranging from Molecular Biology, 2000,vol. 138: Inflammatory disorders hematopoiesis, angiogenesis, andChemokine Protocols. Edited by: A. E. I. Proudfoot, leukocytetrafficking. Members of this T. N. C. Wells, and C. A. Power family areinvolved in a similarly diverse Humana Press Inc., Totowa, NJ range ofpathologies including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G- protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine Accession B15793 secreted proteinsinvolved in biological using assasys known in the art: Methods Immune,Vascular and GROalpha processes ranging from hematopoiesis, in MolecularBiology, 2000, vol. 138: Inflammatory diorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine Accession B15794 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and eotaxin processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis,and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine MIG Accession B15803 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine PF4 Accession B15804 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine I-309 Accession B15805 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine HCC-1 Accession B15806 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine C10 Accession B15807 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine CCR-2 Accession B15808 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine ENA- Accession B15809 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and 78 processes ranging from hematopoiesis, MolecularBiology, 2000, vol. 138: Inflammatory disorders angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine Accession B15810 secreted proteinsinvolved in biological using assasys known in the art: Methods inImmune, Vascular and GRObeta processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: Inflammatory disorders angiogenesis,and leukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot; Members of this family are involved in a T. N. C. Wells, andC. A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human GeneSeq WO0042071 Chemokines are afamily of related small, Chemokine activities can be determinedAutoimmune disorders, chemokine IP-10 Accession B15811 secreted proteinsinvolved in biological using assays known in the art: Methods in Immune,Vascular and processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: Inflammatory disorders angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO0042071 Chemokines are a family of relatedsmall, Chemokine activities can be determined Autoimmune disorders,chemokine Accession B15812 secreted proteins involved in biologicalusing assays known in the art: Methods in Immune, Vascular and SDF1betaprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:Inflammatory disorders angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO0042071 Chemokines are a family of relatedsmall, Chemokine activities can be determined Autoimmune disorders,chemokine GRO Accession B15813 secreted proteins involved in biologicalusing assays known in the art: Methods in Immune, Vascular and alphaprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:Inflammatory disorders angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO0042071 Chemokines are a family of relatedsmall, Chemokine activities can be determined Autoimmune disorders,chemokine Accession B15831 secreted proteins involved in biologicalusing assays known in the art: Methods in Immune, Vascular and MIP1betaprocesses ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:Inflammatory disorders angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, Members of thisfamily are involved in a T. N. C. Wells, and C. A. Power. similarlydiverse range of pathologies Humana Press Inc., Totowa, NJ includinginflammation, allergy, tissue rejection, viral infection, and tumorbiology. The chemokines exert their effects by acting on a family ofseven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. A human C-C GeneSeq U.S. Pat. No. 6,096,300 Chemokines are afamily of related small, Chemokine activities can be determined Cancerchemokine Accession B07939 secreted proteins involved in biologicalusing assays known in the art: Methods in designated processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: exodusangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq U.S. Pat. No. 6,084,071 Chemokines are a family of relatedsmall, Chemokine activities can be determined Chemotaxis, Gene chemokineAccession Y96922 secreted proteins involved in biological using assaysknown in the art: Methods in Therapy, Wound healing L105_7 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq U.S. Pat. No. 6,084,071 Chemokines are a family of relatedsmall, Chemokine activities can be determined Chemotaxis, Gene chemokineAccession Y96923 secreted proteins involved in biological using assaysknown in the art: Methods in Therapy, Wound healing L105_3 processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Humansecondary GeneSeq WO0038706 Chemokines are a family of related small,Chemokine activities can be determined Cancer, Vascular and lymphoidAccession B01434 secreted proteins involved in biological using assaysknown in the art: Methods in Immune disorders chemokine (SLC) processesranging from hematopoiesis, Molecular Biology, 2000, vol. 138:angiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, Members of this family are involved in a T. N. C.Wells, and C. A. Power. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Humannon-ELR GeneSeq WO0029439 Chemokines are a family of related small,Chemokine activities can be determined Immune and Inflammatory CXCchemokine Accession Y96310 secreted proteins involved in biologicalusing assays known in the art: Methods in disorders, Cancer, H174processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:Haemostatic and angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, thrombolytic activity Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human non-ELR GeneSeq WO0029439 Chemokines are a family ofrelated small, Chemokine activities can be determined Immune andInflammatory CXC chemokine Accession Y96311 secreted proteins involvedin biological using assays known in the art: Methods in disorders,Cancer, IP10 processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: haemostatic and angiogenesis, and leukocyte trafficking.Chemokine Protocols. Edited by: A. E. I. Proudfoot, thrombolyticactivity Members of this family are involved in a T. N. C. Wells, and C.A. Power. similarly diverse range of pathologies Humana Press Inc.,Totowa, NJ including inflammation, allergy, tissue rejection, viralinfection, and tumor biology. The chemokines exert their effects byacting on a family of seven transmembrane G-protein-coupled receptors.Over 40 human chemokines have been described, which bind to ~17receptors thus far identified. Human non-ELR GeneSeq WO0029439Chemokines are a family of related small, Chemokine activities can bedetermined Immune and Inflammatory CXC chemokine Accession Y96313secreted proteins involved in biological using assays known in the art:Methods in disorders, Cancer, Mig processes ranging from hematopoiesis,Molecular Biology, 2000, vol. 138: haemostatic and angiogenesis, andleukocyte trafficking. Chemokine Protocols. Edited by: A. E. I.Proudfoot, thrombolytic activity Members of this family are involved ina T. N. C. Wells, and C. A. Power. similarly diverse range ofpathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified. HumanGeneSeq WO0028035 Chemokines are a family of related small, Chemokineactivities can be determined Cancer, wound healing, chemokine AccessionY96280 secreted proteins involved in biological using assays known inthe art: Methods in inflammatory and Ckbeta-7 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: immunoregulatoryangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, disorders Members of this family are involved in aT. N. C. Wells, and C. A. Power. similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq WO0028035 Chemokines are a family of related small, Chemokineactivities can be determined Cancer, wound healing, chemokine MIP-Accession Y96281 secreted proteins involved in biological using assaysknown in the art: Methods in inflammatory and 1alpha processes rangingfrom hematopoiesis, Molecular Biology, 2000, vol. 138: immunoregulatoryangiogenesis, and leukocyte trafficking. Chemokine Protocols. Edited by:A. E. I. Proudfoot, disorders Members of this family are involved in aT. N. C. Wells, and C. A. Power. similarly diverse range of pathologiesHumana Press Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. Human matureGenSeq WO0028035 Chemokines are a family of related small, Chemokineactivities can be determined Cancer, wound healing, chemokine AccessionY96282 secreted proteins involved in biological using assays known inthe art: Methods in inflammatory and Ckbeta-7 processes ranging fromhematopoiesis, Molecular Biology, 2000, vol. 138: immunoregulatory(optionally angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, disorders truncated) Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human GeneSeq WO0018431 Chemokines are a family of relatedsmall, Chemokine activities can be determined Soluble CXCR3 chemokineAccession Y79372 secreted proteins involved in biological using assaysknown in the art: Methods in polypeptides may be receptor CXCR3processes ranging from hematopoiesis, Molecular Biology, 2000, vol. 138:useful for inhibiting angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, chemokine activities andMembers of this family are involved in a T. N. C. Wells, and C. A.Power. viral infection. similarly diverse range of pathologies HumanaPress Inc., Totowa, NJ including inflammation, allergy, tissuerejection, viral infection, and tumor biology. The chemokines exerttheir effects by acting on a family of seven transmembraneG-protein-coupled receptors. Over 40 human chemokines have beendescribed, which bind to ~17 receptors thus far identified. HumanGeneSeq U.S. Pat. No. 6,043,086 Chemokines are a family of relatedsmall, Chemokine activities can be determined Neurological disorders,neurotactin Accession Y53259 secreted proteins involved in biologicalusing assays known in the art: Methods in Immune and respiratorychemokine like processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: disorders domain angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified. Human CC type GeneSeq JP11302298 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer andinfectious chemokine Accession Y57771 secreted proteins involved inbiological using assays known in the art: Methods in diseasesinterleukin C processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: angiogenesis, and leukocyte trafficking. ChemokineProtocols. Edited by: A. E. I. Proudfoot, Members of this family areinvolved in a T. N. C. Wells, and C. A. Power. similarly diverse rangeof pathologies Humana Press Inc., Totowa, NJ including inflammation,allergy, tissue rejection, viral infection, and tumor biology. Thechemokines exert their effects by acting on a family of seventransmembrane G-protein-coupled receptors. Over 40 human chemokines havebeen described, which bind to ~17 receptors thus far identified HumanCKbeta-9 GeneSeq U.S. Pat. No. 6,153,441 Chemokines are a family ofrelated small, Chemokine activities can be determined Cancer,Auto-immune and Accession B50860 secreted proteins involved inbiological using assays known in the art: Methods in inflammatorydisorders, processes ranging from hematopoiesis, Molecular Biology,2000, vol. 138: Cardiovascular disorders angiogenesis, and leukocytetrafficking. Chemokine Protocols. Edited by: A. E. I. Proudfoot, Membersof this family are involved in a T. N. C. Wells, and C. A. Power.similarly diverse range of pathologies Humana Press Inc., Totowa, NJincluding inflammation, allergy, tissue rejection, viral infection, andtumor biology. The chemokines exert their effects by acting on a familyof seven transmembrane G-protein-coupled receptors. Over 40 humanchemokines have been described, which bind to ~17 receptors thus faridentified Preproapolipoprotein GeneSeq WO9637608 Apoa-1 participates inthe reverse Lipid binding activity can be determined Useful forcardiovascular “paris” variant Accession transport of cholesterol fromtissues to using assays known in the art, such as, for disorders,cholesterol W08602 the liver for excretion by promoting example, theCholesterol Efflux Assays of disorders, and cholesterol efflux fromtissues and by Takahaski et al., P. N. A. S., Vol. 96, IssueHyperlipidaemia acting as a cofactor for the lecithin 20, 11358-11363,Sep. 28, 1999. cholesterol acyltransferase (Icat). Preproapolipoprotein5,721,114 Apoa-1 participates in the reverse Lipid binding activity canbe determined Useful for cardiovascular “milano” transport ofcholesterol from tissues to using assays known in the art, such as, fordisorders, cholesterol variant the liver for excretion by promotingexample, the Cholesterol Efflux Assays of disorders, and cholesterolefflux from tissues and by Takahaski et al., P. N. A. S., Vol. 96, IssueHyperlipidaemia acting as a cofactor for the lecithin 20, 11358-11363,Sep. 28, 1999. cholesterol acyltransferase (Icat). Glycodelin-A; GeneSeqWO9628169 Naturally produced female contraceptive Glycodelin-A activitycan be determined Naturally derived Progesterone- Accession that isremoved rapidly from the body using the hemizona assay as described incontraceptive useful for associated W00289 following 2-3 daysproduction. Uses Oehninger, S., Coddington, C. C., Hodgen, G. D., theprevention of endometrial include contraception and Seppala, M (1995)Fertil. Steril. pregnancy. protein 63, 377-383. NOGO-A Genbank NOGOpolypeptides are potent inhibitors Inhibition of Neurite outgrowth.NOGO-A polypeptide Accession of neurite growth. Antagonists to NOGOpolypeptides may antagonists are useful for CAB99248 promote theoutgrowth of neurites, thus the promotion of neural inducingregeneration of neurons. growth, which could be useful in the treatmentof neural disorders and dysfunction due to degenerative diseases ortrauma; useful in the treatment of neoplastic diseases of the CNS;induce regeneration of neurons or to promote the structural plasticityof the CNS. NOGO-B Genbank NOGO polypeptides are potent inhibitorsInhibition of Neurite outgrowth. NOGO-B polypeptide Accession of neuritegrowth. Antagonists to NOGO polypeptides may antagonists are useful forCAB99249 promote the outgrowth of neurites, thus the promotion of neuralinducing regeneration of neurons. growth, which could be useful in thetreatment of neural disorders and dysfunction due to degenerativediseases or trauma; useful in the treatment of neoplastic diseases ofthe CNS; induce regeneration of neurons or to promote the structuralplasticity of the CNS. NOGO-C Genbank NOGO polypeptides are potentinhibitors Inhibition of Neurite outgrowth. NOGO-C polypeptide Accessionof neurite growth. Antagonists to NOGO polypeptides may antagonists areuseful for CAB99250 promote the outgrowth of neurites, thus thepromotion of neural inducing regeneration of neurons. growth, whichcould be useful in the treatment of neural disorders and dysfunction dueto degenerative diseases or trauma; useful in the treatment ofneoplastic diseases of the CNS; induce regeneration of neurons or topromote the structural plasticity of the CNS. NOGO-66 Genbank NOGOpolypeptides are potent inhibitors Inhibition of Neurite outgrowth byNOGO-66 receptor Receptor Accession of neurite growth, and are thoughtto mediating the biological effects of NOGO polypeptides are useful forAAG53612 mediate their effects through the NOGO- polypeptides. SolubleNOGO-66 receptor the promotion of neural 66 Receptor. polypeptides maypromote the outgrowth growth, which could be of neurites, thus inducingregeneration of useful in the treatment of neurons. neural disorders anddysfunction due to degenerative diseases or trauma; useful in thetreatment of neoplastic diseases of the CNS; induce regeneration ofneurons or to promote the structural plasticity of the CNS. Antibodiesspecific U.S. Pat. No. 5,416,197 These antibodies are useful for theCollapsin activity, which is thought to Useful for the promotion of forcollapsin promotion of neurite outgrowth inhibit the outgrowth ofneurites, can be neural growth, which could assayed in the presence ofantibodies be useful in the treatment specific for collapsing usingassays known of neural disorders and in the art, such as, for example,the dysfunction due to collapse assay disclosed by Luo et al.,degenerative diseases or Cell 1993 Oct 22; 75(2): 217-27 trauma.Humanized Anti- WO9845331 These agents have anti-inflammatory and VEGFactivity can be determined using Promotion of growth and VEGFAntibodies, anti-cancer applications assays known in the art, such asthose proliferation of cells, such and fragments disclosed inInternational Publication No. as vascular endothelial thereof WO0045835,for example. cells. Antagonists may be useful as anti-angiogenic agents,and may be applicable for cancer Humanized Anti- WO0029584 These agentshave anti-inflammatory and VEGF activity can be determined usingPromotion of growth and VEGF Antibodies, anti-cancer applications assaysknown in the art, such as those proliferation of cells, such andfragments disclosed in International Publication No. as vascularendothelial thereof WO0045835, for example. cells. Antagonists may beuseful as anti-angiogenic agents, and may be applicable for cancerMembrane bound GeneSeq. WO9963088 Cancer, Immune Disorders Theseproteins can be used for linking Activities can be proteins Accessionbioactive molecules to cells and for determined using assayY66631-Y66765 modulating biological activities of cells, known in theart, suchas, using the polypeptides for specific for example, the assaystargeting. The polypeptide targeting can disclosed in International beused to kill the target cells, e.g. for the Publication No. treatment ofcancers. These proteins are WO0121658. useful for the treatment ofimmune system disorders. Secreted and GenSeq WO0053756 Cancer, ImmuneDisorders These proteins can be used for linking Activities can beTransmembrane Accession bioactive molecules to cells and for determinedusing assay polypeptides B44241-B44334 modulating biological activitiesof cells, known in the art, suchas, using the polypeptides for specificfor example, the assays targeting. The polypeptide targeting candisclosed in International be used to kill the target cells, e.g. forthe Publication No. treatment of cancers. These proteins are WO0121658useful for the treatment of immune system disorders. Secreted andGeneSeq WO9946281 Cancer, Immune Disorders These proteins can be usedfor linking Activities can be Transmembrane Accession bioactivemolecules to cells and for determined using assay polypeptidesY41685-Y41774 modulating biological activities of cells, known in theart, suchas, using the polypeptides for specific for example, the assaystargeting. The polypeptide targeting can disclosed in International beused to kill the target cells, e.g. for the Publication No. treatment ofcancers. These proteins are WO0121658 useful for the treatment of immunesystem disorders.Conjugation and Coupling

The present invention provides therapeutic agents comprising an elasticpeptide component and a therapeutic component, such as therapeuticproteins listed in herein, including Table 1, as well as a GLP-1receptor agonists, insulin, Factor VII/VIIa, and functional analogs asdescribed. Such agents may be prepared by recombinant technology and/orchemical coupling (e.g., conjugation).

A recombinantly-produced elastic peptide fusion protein, in accordancewith certain embodiments of the invention, includes the elastic peptidecomponent and the therapeutic component associated with one another bygenetic fusion. For example, the fusion protein may be generated bytranslation of a polynucleotide encoding the therapeutic componentcloned in-frame with the elastic peptide component (or vice versa). Suchan elastic peptide fusion protein may contain one or more copies of thetherapeutic component attached to the N-terminus and/or the C-terminusof the elastic peptide component. In some embodiments, the therapeuticproteinacious component is attached to both the N- and C-terminus of theelastic peptide component and the fusion protein may contain one or moreequivalents of the therapeutic component on either or both ends of theelastic peptide component.

In certain embodiments, the elastic peptide component and thetherapeutic components can be fused using a linker peptide of variouslengths to provide greater physical separation and allow more spatialmobility between the fused portions, and thus maximize the accessibilityof the therapeutic component, for instance, for binding to its cognatereceptor. The linker peptide may consist of amino acids that areflexible or more rigid. For example, a flexible linker may include aminoacids having relatively small side chains, and which may be hydrophilic.Without limitation, the flexible linker may contain a stretch of glycineand/or serine residues. More rigid linkers may contain, for example,more sterically hindering amino acid side chains, such as (withoutlimitation) tyrosine or histidine. The linker may be less than about 50,40, 30, 20, 10, or 5 amino acid residues. The linker can be covalentlylinked to and between an elastic peptide component and a therapeuticcomponent, for example, via recombinant fusion.

The linker or peptide spacer may be protease-cleavable or non-cleavable.By way of example, cleavable peptide spacers include, withoutlimitation, a peptide sequence recognized by proteases (in vitro or invivo) of varying type, such as Tev, thrombin, factor Xa, plasmin (bloodproteases), metalloproteases, cathepsins (e.g., GFLG, etc.), andproteases found in other corporeal compartments. In some embodimentsemploying cleavable linkers, the fusion protein (“the therapeuticagent”) may be inactive, less active, or less potent as a fusion, whichis then activated upon cleavage of the spacer in vivo. Alternatively,where the therapeutic agent is sufficiently active as a fusion, anon-cleavable spacer may be employed. The non-cleavable spacer may be ofany suitable type, including, for example, non-cleavable spacer moietieshaving the formula [(Gly)n-Ser]m (SEQ ID NO.: 22) where n is from 1 to4, inclusive, and m is from 1 to 4, inclusive. Alternatively, a shortelastic peptide sequence different than the backbone elastic peptidecould be employed instead of a linker or spacer, while accomplishing thenecessary effect.

In still other embodiments, the therapeutic agent is a recombinantfusion having a therapeutic component flanked on each terminus by anelastic peptide component. At least one of said elastic peptidecomponents may be attached via a cleavable spacer, such that thetherapeutic component is inactive, but activated in vivo by proteolyticremoval of a single elastic peptide component. The resulting singleelastic peptide fusion being active, and having an enhanced half-life(or other property described herein) in vivo.

In other embodiments, the present invention provides chemical conjugatesof the elastic peptide component and the therapeutic component. Theconjugates can be made by chemically coupling an elastic peptidecomponent to a therapeutic component by any number of methods well knownin the art (See e.g. Nilsson et al., 2005, Ann Rev Biophys Bio Structure34: 91-118). In some embodiments, the chemical conjugate can be formedby covalently linking the therapeutic component to the elastic peptidecomponent, directly or through a short or long linker moiety, throughone or more functional groups on the therapeutic proteinaciouscomponent, e.g., amine, carboxyl, phenyl, thiol or hydroxyl groups, toform a covalent conjugate. Various conventional linkers can be used,e.g., diisocyanates, diisothiocyanates, carbodiimides, bis(hydroxysuccinimide) esters, maleimide-hydroxysuccinimide esters,glutaraldehyde and the like.

Non-peptide chemical spacers can additionally be of any suitable type,including for example, by functional linkers described in BioconjugateTechniques, Greg T. Hermanson, published by Academic Press, Inc., 1995,and those specified in the Cross-Linking Reagents Technical Handbook,available from Pierce Biotechnology, Inc. (Rockford, Ill.), thedisclosures of which are hereby incorporated by reference, in theirrespective entireties. Illustrative chemical spacers includehomobifunctional linkers that can attach to amine groups of Lys, as wellas heterobifunctional linkers that can attach to Cys at one terminus,and to Lys at the other terminus.

In certain embodiments, relatively small ELP components (e.g., ELPcomponents of less than about 30 kDa, 25 kDa, 20 kDa, 15 kDa, or 10kDa), that do not transition at room temperature (or human bodytemperature, e.g., Tt>37° C.), are chemically coupled or crosslinked.For example, two relatively small ELP components, having the same ordifferent properties, may be chemically coupled. Such coupling, in someembodiments, may take place in vivo, by the addition of a singlecysteine residue at or around the C-terminus of the ELP. Such ELPcomponents may each be fused to one or more therapeutic components, soas to increase activity or avidity at the target.

Polynucleotides, Vectors, and Host Cells

In another aspect, the invention provides polynucleotides comprising anucleotide sequence encoding the therapeutic agent of the invention.Such polynucleotides further comprise, in addition to sequences encodingthe elastic peptide and therapeutic components, one or more expressioncontrol elements. For example, the polynucleotide, may comprise one ormore promoters or transcriptional enhancers, ribosomal binding sites,transcription termination signals, and polyadenylation signals, asexpression control elements. The polynucleotide may be inserted withinany suitable vector, which may be contained within any suitable hostcell for expression.

A vector comprising the polynucleotide can be introduced into a cell forexpression of the therapeutic agent. The vector can remain episomal orbecome chromosomally integrated, as long as the insert encoding thetherapeutic agent can be transcribed. Vectors can be constructed bystandard recombinant DNA technology. Vectors can be plasmids, phages,cosmids, phagemids, viruses, or any other types known in the art, whichare used for replication and expression in prokaryotic or eukaryoticcells. It will be appreciated by one of skill in the art that a widevariety of components known in the art (such as expression controlelements) may be included in such vectors, including a wide variety oftranscription signals, such as promoters and other sequences thatregulate the binding of RNA polymerase onto the promoter. Any promoterknown to be effective in the cells in which the vector will be expressedcan be used to initiate expression of the therapeutic agent. Suitablepromoters may be inducible or constitutive. Examples of suitablepromoters include the SV40 early promoter region, the promoter containedin the 3′ long terminal repeat of Rous sarcoma virus, the HSV-1 (herpessimplex virus-1) thymidine kinase promoter, the regulatory sequences ofthe metallothionein gene, etc., as well as the following animaltranscriptional control regions, which exhibit tissue specificity andhave been utilized in transgenic animals: elastase I gene control regionwhich is active in pancreatic acinar cells; insulin gene control regionwhich is active in pancreatic beta cells, immunoglobulin gene controlregion which is active in lymphoid cells, mouse mammary tumor viruscontrol region which is active in testicular, breast, lymphoid and mastcells, albumin gene control region which is active in liver,alpha-fetoprotein gene control region which is active in liver, alpha1-antitrypsin gene control region which is active in the liver,beta-globin gene control region which is active in erythroid cells,myelin basic protein gene control region which is active inoligodendrocyte cells in the brain, myosin light chain-2 gene controlregion which is active in skeletal muscle, and gonadotropin releasinghormone gene control region which is active in the hypothalamus.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising the therapeutic agents of the invention (as described above)together with a pharmaceutically acceptable carrier or excipient. Suchpharmaceutical compositions may be employed in the methods of treatmentas described above, for each of the therapeutic proteins, e.g., thetherapeutic proteins listed in Table 1, GLP-1 receptor agonists,insulin, and Factor VII/VIIa embodiments.

The therapeutic agents of the invention may overcome certaindeficiencies of peptide agents when administered (e.g., parenterally),including in some embodiments, the limitation that such peptides may beeasily metabolized by plasma proteases or cleared from circulation bykidney filtration. Traditionally, the oral route of administration ofpeptide agents may also be problematic, because in addition toproteolysis in the stomach, the high acidity of the stomach destroyssuch peptide agents before they reach their intended target tissue.Peptides and peptide fragments produced by the action of gastric andpancreatic enzymes are cleaved by exo and endopeptidases in theintestinal brush border membrane to yield di and tripeptides, and evenif proteolysis by pancreatic enzymes is avoided, polypeptides aresubject to degradation by brush border peptidases. Any of the peptideagents that survive passage through the stomach are further subjected tometabolism in the intestinal mucosa where a penetration barrier preventsentry into the cells. In certain embodiments, the therapeutic agents ofthe invention may overcome such deficiencies, and provide compositionalforms having enhanced efficacy, bioavailability, therapeutic half-life,persistence, degradation assistance, etc. The therapeutic agents of theinvention thus include oral and parenteral dose forms, as well asvarious other dose forms, by which peptide agents can be utilized in ahighly effective manner. For example, in some embodiments, such agentsmay achieve high mucosal absorption, and the concomitant ability to uselower doses to elicit an optimum therapeutic effect.

The therapeutic agents of the present invention may be administered insmaller doses and/or less frequently than unfused or unconjugatedcounterparts. While one of skill in the art can determine the desirabledose in each case, a suitable dose of the therapeutic agent forachievement of therapeutic benefit, may, for example, be in a range ofabout 1 microgram (μg) to about 100 milligrams (mg) per kilogram bodyweight of the recipient per day, preferably in a range of about 10 μg toabout 50 mg per kilogram body weight per day and most preferably in arange of about 10 μg to about 50 mg per kilogram body weight per day.The desired dose may be presented as one dose or two or more sub-dosesadministered at appropriate intervals throughout the day. Thesesub-doses can be administered in unit dosage forms, for example,containing from about 10 μg to about 1000 mg, preferably from about 50μg to about 500 mg, and most preferably from about 50 μg to about 250 mgof active ingredient per unit dosage form. Alternatively, if thecondition of the recipient so requires, the doses may be administered asa continuous infusion.

The mode of administration and dosage forms will of course affect thetherapeutic amount of the peptide active therapeutic agent that isdesirable and efficacious for a given treatment application. Forexample, orally administered dosages can be at least twice, e.g., 2-10times, the dosage levels used in parenteral administration methods.

The therapeutic agents of the invention may be administered per se aswell as in various forms including pharmaceutically acceptable esters,salts, and other physiologically functional derivatives thereof. Thepresent invention also contemplates pharmaceutical formulations, bothfor veterinary and for human medical use, which include therapeuticagents of the invention. In such pharmaceutical and medicamentformulations, the therapeutic agents can be used together with one ormore pharmaceutically acceptable carrier(s) therefore and optionally anyother therapeutic ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not unduly deleterious to the recipient thereof.The therapeutic agents are provided in an amount effective to achievethe desired pharmacological effect, as described above, and in aquantity appropriate to achieve the desired daily dose.

The formulations of the therapeutic agent include those suitable forparenteral as well as non-parenteral administration, and specificadministration modalities include oral, rectal, buccal, topical, nasal,ophthalmic, subcutaneous, intramuscular, intravenous, transdermal,intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial,lymphatic, vaginal, and intra-uterine administration. Formulationssuitable for oral and parenteral administration are preferred.

When the therapeutic agent is used in a formulation including a liquidsolution, the formulation advantageously can be administered orally orparenterally. When the therapeutic agent is employed in a liquidsuspension formulation or as a powder in a biocompatible carrierformulation, the formulation may be advantageously administered orally,rectally, or bronchially.

When the therapeutic agent is used directly in the form of a powderedsolid, the active agent can be advantageously administered orally.Alternatively, it may be administered bronchially, via nebulization ofthe powder in a carrier gas, to form a gaseous dispersion of the powderwhich is inspired by the patient from a breathing circuit comprising asuitable nebulizer device.

The formulations comprising the therapeutic agent of the presentinvention may conveniently be presented in unit dosage forms and may beprepared by any of the methods well known in the art of pharmacy. Suchmethods generally include the step of bringing the therapeutic agentsinto association with a carrier which constitutes one or more accessoryingredients. Typically, the formulations are prepared by uniformly andintimately bringing the therapeutic agent into association with a liquidcarrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product into dosage forms of the desiredformulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets, tablets, or lozenges, eachcontaining a predetermined amount of the active ingredient as a powderor granules; or a suspension in an aqueous liquor or a non-aqueousliquid, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine, with the therapeutic agent being in afree-flowing form such as a powder or granules which optionally is mixedwith a binder, disintegrant, lubricant, inert diluent, surface activeagent, or discharging agent. Molded tablets comprised of a mixture ofthe powdered peptide active therapeutic agent-elastic peptideconstruct(s) with a suitable carrier may be made by molding in asuitable machine.

A syrup may be made by adding the peptide active therapeutic agent-ELPconstruct(s) to a concentrated aqueous solution of a sugar, for examplesucrose, to which may also be added any accessory ingredient(s). Suchaccessory ingredient(s) may include flavorings, suitable preservative,agents to retard crystallization of the sugar, and agents to increasethe solubility of any other ingredient, such as a polyhydroxy alcohol,for example glycerol or sorbitol.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the therapeutic agent, whichpreferably is isotonic with the blood of the recipient (e.g.,physiological saline solution). Such formulations may include suspendingagents and thickening agents or other microparticulate systems which aredesigned to target the peptide active therapeutic agent to bloodcomponents or one or more organs. The formulations may be presented inunit-dose or multi-dose form.

Nasal spray formulations comprise purified aqueous solutions of thetherapeutic agent with preservative agents and isotonic agents. Suchformulations are preferably adjusted to a pH and isotonic statecompatible with the nasal mucus membranes.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acid.

Topical formulations comprise the therapeutic agent dissolved orsuspended in one or more media, such as mineral oil, petroleum,polyhydroxy alcohols, or other bases used for topical pharmaceuticalformulations.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, disintegrants,surface active agents, thickeners, lubricants, preservatives (includingantioxidants), and the like.

The features and advantages of the present invention are more fullyshown with respect to the following non-limiting examples.

EXAMPLES Example 1 Construction of Various ELP Component Constructs

Cloning steps were conducted in Escherichia coli strain XL1-Blue (recA1, endA1, gyrA96, thi-1, hsdR17 (r_(k) ⁻, m_(k)+), supE44, relA1,Iac[F′, proAB, /αcl^(q)ZΔM15, Tn10 (Tet^(r))] (Stratagene La Jolla,Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning vector forthe ELP construction (Meyer and Chilkoti, Nat. Biotechnol.,17(11):1112-5, 1999). Modified forms of pET15b and pET24d vectors(Novagen) were used to express ELP and ELF-fusion proteins in BL21 Star(DE3) strain (F⁻, ompT, hsdS_(B) (r_(B) ⁻m_(B) ⁻), gal, dcm, rne131,(DE3)) (Invitrogen Carlsbed, Calif.) or BLR(DE3) ompT, hsdS_(B) (r_(B)⁻m_(B) ⁻), gal, dcm, Δ(srl-recA) 306:Tn10(TcR)(DE3)) (Novagen Madison,Wis.). Synthetic DNA oligos were purchased from Integrated DNATechnologies, Coralville, Iowa. All vector constructs were made usingstandard molecular biology protocols (e.g., Current Protocols inMolecular Biology, ed. Ausubel, et al., 1995).

Construction of ELP1 [V₅A₂G₃] Gene Series

The ELP1 [V₅A₂G₃] series designate polypeptides containing multiplerepeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X isvaline, alanine, and glycine at a relative ratio of 5:2:3.

The ELP1 [V₅A₂G₃] series monomer, ELP1 [V₅A₂G₃-10], was created byannealing four 5′ phosphorylated, PAGE purified synthetic oligos to formdouble stranded DNA with EcoRI and HindIII compatible ends (Meyer andChilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). The oligos wereannealed in a 1 μM mixture of the four oligos in 50 μl IX ligase buffer(Invitrogen) to 95° C. in a heating block than the block was allowed tocool slowly to room temperature. The ELP1 [V₅A₂G₃-10]/EcoRI-HindIII DNAsegment was ligated into a pUC19 vector digested with EcoRI and HindIIIand CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [V₅A₂G₃-10].Building of the ELP1 [V₅A₂G₃] series library began by inserting ELP1[V₅A₂G₃-10] PflMI/BgII fragment from pUC19-ELP1 [V₅A₂G₃-10] intopUC19-ELP1 [V₅A₂G₃-10] linearized with PflMI and dephosphorylated withCIAP to create pUC19-ELP1 [V₅A₂G₃-20]. pUC19-ELP1 [V₅A₂G₃-20] was thenbuilt up to pUC19-ELP1 [V₅A₂G₃-30] and pUC19-ELP1 [V₅A₂G₃-40] byligating ELP1 [V₅A₂G₃-10] or ELP1 [V₅A₂G₃-20] PflMI/BgII fragmentsrespectively into PflMI digested pUC 19-ELP1 [V₅A₂G₃-20]. This procedurewas used to expand the ELP1 [V₅A₂G₃] series to create pUC19-ELP1[V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90] and pUC19-ELP1 [V₅A₂G₃-180] genes.

Construction of ELP1 [K₁V₂F₁] Gene Series

The ELP1 [K₁V₂F₁] series designate polypeptides containing multiplerepeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X islysine, valine, and phenylalanine at a relative ratio of 1:2:1.

The ELP1 [K₁V₂F₁] series monomer, ELP1 [K₁V₂F₁-4], was created byannealing two 5′ phosphorylated, PAGE purified synthetic oligos to formdouble stranded DNA with EcoRI and HindIII compatible ends (Meyer andChilkoti, 1999). The oligos were annealed in a 1 μM mixture of the fouroligos in 50 μl 1× ligase buffer (Invitrogen) to 95° C. in a heatingblock then the block was allowed to cool slowly to room temperature. TheELP1 [K₁V₂F₁-4]/EcoRI-HindIII DNA segment was ligated into a pUC19vector digested with EcoRI and HindIII and CIAP dephosphorylated(Invitrogen) to form pUC19-ELP1 [K₁V₂F₁-4]. Building of the ELP1[K₁V₂F₁] series library began by inserting ELP1 [K₁V₂F₁-4] PflM1Bgl1fragment from pUC19-ELP1 [K₁V₂F₁-4] into pUC19-ELP1 [K₁V₂F₁-4]linearized with PflM1 and dephosphorylated with CIAP to createpUC19-ELP1 [K₁V₂F₁-8]. Using the same procedure the ELP1 [K₁V₂F₁] serieswas doubled at each ligation to form pUC19-ELP1 [K₁V₂F₁-16], pUC19-ELP1[K₁V₂F₁-32], pUC19-ELP1 [K₁V₂F₁-64] and pUC19-ELP1 [K₁V₂F₁-128].

Construction of ELP1 [K₁V₇F₁] Gene Series

The ELP1 [K₁V₇F₁] series designate polypeptides containing multiplerepeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X islysine, valine, and phenylalanine at a relative ratio of 1:7:1.

The ELP1 [K₁V₇F₁] series monomer, ELP1 [K₁V₇F₁-9], was created byannealing four 5′ phosphorylated, PAGE purified synthetic oligos to formdouble stranded DNA with Pfl/MI and HindIII compatible ends. The ELP1[K₁V₇F₁-9] DNA segment was than ligated into PflM1/HindIIIdephosphorylated PUC19-ELP1 [V₅A₂G₃-180] vector thereby substitutingELP1 [V₅A₂G₃-180] for ELP1 [K₁V₇F₁-9] to create the pUC19-ELP1[K₁V₇F₁-9] monomer. The ELP1 [K₁V₇F₁] series was expanded in the samemanner as the ELP1 [K₁V₇F₁] series to create pUC19-ELP1 [K₁V₇F₁-18],PUC19-ELP1 [K₁V₇F₁-36], pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1[K₁V₇F₁-144].

Construction of ELP1 [V] Gene Series

The ELP1 [V] series designate polypeptides containing multiple repeatingunits of the pentapeptide VPGXG (SEQ ID NO: 3), where X is exclusivelyvaline.

The ELP1 [V] series monomer, ELP1 [V-5], was created by annealing two 5′phosphorylated, PAGE purified synthetic oligos to form double strandedDNA with EcoRI and HindIII compatible ends. The ELP1 [V-5] DNA segmentwas than ligated into EcoRI/HindIII dephosphorylated pUC19 vector tocreate the pUC19-ELP1 [V-5] monomer. The ELP1 [V] series was created inthe same manner as the ELP1 [V₅A₂G₃] series, ultimately expandingpUC19-ELP1 [V-5] to pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120].

Construction of ELP2 Gene Series

The ELP2 series designate polypeptides containing multiple repeatingunits of the pentapeptide AVGVP.

The ELP2 series monomer, ELP2 [5], was created by annealing two 5′phosphorylated, PAGE purified synthetic oligos to form double strandedDNA with EcoRI and HindIII compatible ends. The ELP2 [5] DNA segment wasthan ligated into EcoRI/HindIII dephosphorylated pUC19 vector to createthe pUC19-ELP2[5] monomer. The ELP2 series was expanded in the samemanner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP2[10], pUC19-ELP2[30], pUC 19-ELP2 [60] and pUC 19-ELP2 [120].

Construction of ELP3 [V] Gene Series

The ELP3 [V] series designate polypeptides containing multiple repeatingunits of the pentapeptide IPGXG (SEQ ID NO: 5), where X is exclusivelyvaline.

The ELP3 [V] series monomer, ELP3 [V-5], was created by annealing two 5′phosphorylated, PAGE purified synthetic oligos to form double strandedDNA with PfLM1 amino terminal and GGC carboxyl terminal compatible endsdue to the lack of a convenient carboxyl terminal restriction site butstill enable seamless addition of the monomer. The ELP3 [V-5] DNAsegment was then ligated into PflM1/BgII dephosphorylatedpUC19-ELP4[V-5], thereby substituting ELP4 [V-5] for ELP3 [V-5] tocreate the pUC19-ELP3 [V-5] monomer. The ELP3 [V] series was expanded byligating the annealed ELP3 oligos into pUC19-ELP3[V-5] digested withPflMI. Each ligation expands the ELP3 [V] series by 5 to create ELP3[V-10], ELP3 [V-15], etc.

Construction of the ELP4 [V] Gene Series

The ELP4 [V] series designate polypeptides containing multiple repeatingunits of the pentapeptide LPGXG (SEQ ID NO: 7), where X is exclusivelyvaline.

The ELP4 [V] series monomer, ELP4 [V-5], was created by annealing two 5′phosphorylated, PAGE purified synthetic oligos to form double strandedDNA with EcoRI and HindIII compatible ends. The ELP4 [V-5] DNA segmentwas than ligated into EcoRI/HindIII dephosphorylated pUC19 vector tocreate the pUC19-ELP4[V-5] monomer. The ELP4 [V] series was expanded inthe same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP4[V-10],pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].

The ELP genes were also inserted into other vectors such as pET15b-SDO,pET15b-SD3, pET15b-SDS, pET15b-SD6, and pET24d-SD21. The pET vectorseries are available from Novagen, San Diego, Calif.

The pET15b-SDO vector was formed by modifying the pET15b vector usingSDO double-stranded DNA segment containing the multicloning restrictionsite (Sacl-Ndel-Ncol-Xhol-SnaBl-BamHl). The SDO double-stranded DNAsegment had Xbal and BamHl compatible ends and was ligated intoXbal/BamHI linearized and 5′-dephosphorylated pET15b to form thepet15b-SDO vector.

The pET15b-SD3 vector was formed by modifying the pET15b-SDO vectorusing SD3 double-stranded DNA segment containing a Sfil restriction siteupstream of a hinge region-thrombin cleavage site followed by themulticloning site (Ndel-Ncol-Xhol-SnaBI-BamHI). The SD3 double-strandedDNA segment had Sacl and Ndel compatible ends and was ligated intoSacl/Ndel linearized and 5′-dephosphorylated pET15b-SDO to form thepET15b-SD3 vector.

The pET15b-SD5 vector was formed by modifying the pET15b-SD3 vectorusing the SD5 double-stranded DNA segment containing a SM restrictionsite upstream of a thrombin cleavage site followed by a hinge and themulticloning site (Ndel-Ncol-Xhol-SnaBI-BamI). The SD5 double-strandedDNA segment had Sfil and Ndel compatible ends and was ligated intoSfil/Ndel linearized and 5′-dephosphorylated pET15b-SD3 to form thepET15b-SD5 vector.

The pET15b-SD6 vector was formed by modifying the pET15b-SD3 vectorusing the SD6 double-stranded DNA segment containing a Sfil restrictionsite upstream of a linker region-TEV cleavage site followed by themulticloning site (Ndel-Ncol-Xhol-SnaBI-BamHI). The SD6 double-strandedDNA segment had Sfil and Nhel compatible ends and was ligated intoSfil/Ndel linearized and 5′-dephosphorylated pET15b-SD3 to form thepET15b-SD6 vector.

The pET24d-SD21 vector was formed by modifying the pET24d vector usingthe SD21 double-stranded DNA segment with Ncol and Nhel compatible ends.The SD21 double-stranded DNA segment was ligated into Ncol/Nhellinearized and 5′ dephosphorylated pET24d to create the pET24d-SD21vector, which contained a new multi-cloning siteNcol-Sfil-Nhel-BamHI-EcoRI-Sacl-Sall-HindIII-Notl-Xhol with two stopcodons directly after the Sfil site for insertion and expression of ELPwith the minimum number of extra amino acids.

The pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90], and pUC19-ELP1[V₅A₂G₃-180] plasmids produced in XL1-Blue were digested with PflMI andBgII, and the ELP-containing fragments were ligated into the Sfil siteof the pET15b-SD3 expression vector as described hereinabove to createpET15b-SD3-ELP1 [V₅A₂G₃-60], pET15b-SD5-ELP1 [V₅A₂G₃-90] andpET15b-SD5-ELP1 [V₅A₂G₃-180], respectively.

The pUC19-ELP1 [V₅A₂G₃-90], pUC19-ELP1 [V₅A₂G₃-180], pUC19-ELP1 [V-60]and pUC19-ELP1 [V-120] plasmids produced in XL1-Blue were digested withPflMI and BgII, and the ELP-containing fragments were ligated into theSfil site of the pET15b-SD5 expression vector as described hereinaboveto create pET15b-SD5-ELP1 [V₅A₂G₃-90], pET15b-SD5-ELP1 [V₅A₂G₃-180],pET15b-SD5-ELP1 [V-60] and pET15b-SD5-ELP1 [V-120], respectively.

The pUC19-ELP1 [V₅A₂G₃-90] plasmid produced in XL1-Blue was digestedwith PflMI and BgII, and the ELP-containing fragment was ligated intothe Sfil site of the pET15b-SD6 expression vector as describedhereinabove to create pET15b-SD6-ELP1 [V₅A₂G₃-90].

The pUC19-ELP1 [K₁V₂F₁-64], and pUC19-ELP1 [K₁V₂F₁-128] plasmidsproduced in XL1-Blue were digested with PflMI and BgII, and theELF-containing fragments were ligated into the Sfil site of thepET24d-SD21 expression vector as described hereinabove to createpET24d-SD21-ELP1 [K₁V₂F₁-64] and pET24d-SD21-ELP1 [K₁V₂F₁-128],respectively.

The pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144] plasmids producedin XL1-Blue were digested with PflMI and BgII, and the ELF-containingfragments were ligated into the Sfil site of the pET24d-SD21 expressionvector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₇F₁-72],pET24d-SD21-ELP1 [K₁V₇F₁-144], respectively.

The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in XL1-Bluewere digested with Ncol and HindIII, and the ELP-containing fragmentswere ligated into the Ncol and HindIII sites of the pET24d-SD21expression vector as described hereinabove to createpET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120], respectively.

The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced in XL1-Bluewere digested with Ncol and HindIII, and the ELP-containing fragmentswere ligated into the Ncol and HindIII sites of the pET24d-SD21expression vector as described hereinabove to createpET24d-SD21-ELP4[V-60], pET24d-SD21-ELP4[V-120], respectively.

Example 2 Isolation and Purification of Fusion Proteins ContainingInsulin A Peptide (InsA)

ELP-InsA fusion proteins included the following:

Insulin A peptide and ELP1 [V-60] polypeptide with an enterokinaseprotease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-90] polypeptide with an enterokinaseprotease cleavage site therebetween.

Insulin A peptide and ELP1 [V-120] polypeptide with an enterokinaseprotease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-180] polypeptide with an enterokinaseprotease cleavage site therebetween.

A single colony of E. coli strain BLR (DE3) (Novagen) containing therespective ELP-InsA fusion protein was inoculated into 5 ml CircleGrow(Q-BIOgene, San Diego, Calif.) supplemented with 100 μg/ml ampicillin(Sigma) and grown at 37° C. with shaking at 250 rpm for 5 hours. The 5ml culture was then inoculated into a 500 ml culture and allowed to growat 25° C. for 16 hours before inducing with 1 mM IPTG for 4 hours at 25°C. The culture was harvested and suspended in 40 ml 20 mM Tris-HCl pH7.4, 50 mM NaCl, 1 mM DTT and 1 Complete EDTA free Protease inhibitorpellet (Roche, Indianapolis, Ind.). Cells were lysed by ultrasonicdisruption on ice for 3 minutes, which consisted of 10 seconds bursts at35% power separated by 30 second cooling down intervals. Cell debris wasremoved by centrifugation at 20,000 g, 4° C. for 30 minutes.

Inverse phase transition was induced by adding NaCl to the cell lysateat room temperature to achieve a final concentration of 1.0 M therein,followed by centrifugation at 20,000 g for 15 minutes at roomtemperature. The resulting pellet contained the respective ELP-InsAfusion protein and non-specifically NaCl precipitated proteins.

The pellet was re-suspended in 40 ml ice-cold ml 20 mM Tris-HCl pH 7.4,50 mM NaCl, 1 mM DTT and re-centrifuged at 20,000 g, 4° C. for 15minutes to remove the non-specifically NaCl precipitated proteins. Theinverse transition cycle was repeated two additional times to increasethe purity of the respective ELP-InsA fusion protein and reduce thefinal volume to 0.5 ml.

Example 3 Half-Life of ELP1

The pharmacokinetics of ELP1 were determined by intravenouslyadministering [¹⁴C]ELP1 to nude mice (Balb/c nu/nu) bearing a leg/flankFaDu xenograft and collecting blood samples at various time intervalsafter administration. The blood pharmacokinetics exhibited acharacteristic distribution and elimination response for largemacromolecules, which was well described by a bi-exponential process.

The plasma concentration time-course curve was fit to the analyticalsolution of a two-compartment model to approximate both an eliminationand distribution response. Certain pharmakinetic parameters are shown inTable 1 below. The distribution volume of the ELP (1.338 μl) was nearlyidentical to the hypothetical plasma volume of 1.363 μl (Barbee, R. W.,et al., Am. J. Physio. 263(3) (1992) R728-R733), indicating that the ELPdid not rapidly distribute or bind to specific organs and tissuesdirectly after administration. The AUC is a measure of the cumulativeexposure to ELP in the central compartment or the blood plasma. The bodyclearance is defined as the rate of ELP elimination in the body relativeto its plasma concentration and is the summation of clearance throughall organs including the kidney, liver and others.

TABLE 1 Pharmacokinetic parameters calculated for [¹⁴C]ELP1 AUC (mg k₁(hr⁻¹) k₂ (hr⁻¹) k_(e) (hr⁻¹) V_(d) (μL) ELP hr/ml) Cl_(B) (μL/hr)ELP1-150 3.54 1.99 0.24 1.338 7.1 317

The mass transfer rate constants are from a standard two-compartmentmodel (k₁; from central to peripheral compartment; k₂, from peripheralto central compartment; and k_(e), elimination from centralcompartment). The distribution volume (V_(d)), central compartmentconcentration time-course area under the curve (AUC) and body clearance(Cl_(B)) are displayed. Data are shown as the mean values (n=5, exceptV_(d) and initial plasma concentration (C_(O)) was calculated from asimilar cohort with n=3).

Example 4 Biodistribution of ELPs in Nude Mice

¹⁴C Labeled ELP1-150 and/or ¹⁴C Labeled ELP2-160

¹⁴C labeled ELP1-150 and/or ¹⁴C labeled ELP2-160 were administered tonude mice with a FaDu tumor (mean +/−SD, n=6). The tumor was heated postadministration of the ELP in a water bath at 41.5° C. The distributionwas highest to the organs with the highest blood content: liver,kidneys, spleen, and lungs.

¹⁴C Labeled ELP2-[V₁A₈G₇-160]

¹⁴C labeled ELP2-[V₁A₈G₇-160] (T_(t)>60° C.) was administered to nudemice for a plasma concentration of 15 μM. ELP concentrations weredetermined following 1 hour of heating (41° C.) of an implanted FaDutumor, located in the right hind leg of the nude mouse. Data are shownas the mean, plus the 95% confidence interval. N=6.

ELP concentration was measured 1.5 hours following systemicadministration of ¹⁴C labeled ELP2-[V₁A₈G₇-160]. The highestdistribution is seen in organs with the highest blood content: liver,kidneys, spleen, and lungs.

Example 5 Exendin-4 ELP Fusion

The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was reversetranslated from the amino acid sequence using codons optimized for E.coli expression. The DNA sequence encoding Exendin-4 was constructed byannealing together synthetic oligonucleotides with overhanging 5′ and 3′ends compatible with the restriction sites Ndel and Xhol in the plasmidpET24d-ELP1-90 (FIG. 1). This plasmid was digested with the restrictionenzymes Ndel and Xhol and the annealed DNA sequence was ligated into thecut vector. Insertion was confirmed by restriction digest and DNAsequencing. The resulting plasmid was designated as pET24d-Ex-4 ELP1-90(FIG. 2A), and the sequence of the resulting Exendin-4-ELP fusion shownin FIG. 2B. Primers for construction of the fusion are also indicated.

pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain BRL(Invitrogen) and selected transformants were grown in media 3 (1.2%Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids, 2% glycerol,2.313 g Potassium phosphate dibasic/L, 12.541 g Potassium phosphatemonobasic/L) in shake flasks. Production proceeded by autoinduction byinoculating 1 OD cells into 1 L of media 3 and allowing growth toproceed for 17 hr at 37° C. without addition of inducer. The product wasrecovered by collection of the cell pellet, sonicated to disrupt thecells and recovered by thermal and/or salt induced transition modulatedby the ELP moiety (Improved Non-chromatographic Purification of aRecombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo Lim,Kimberly Trabbic-Carlson, J. Andrew MacKay, and Ashutosh Chilkoti.Biomacromolecules 2007, 8, 1417-1424).

This example is with the ELP designated 1-90. This is based on the VPGXG(SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat whereX is a V, G, A and W in the ratio 4:3:2:1.

[(VPGXG)10]₉ where the X residue in the ten sequential iterations of therepeat unit (numerical subscript) can be described as[(V_(1, 4, 5, 6, 10)G_(2, 7, 9)A_(3, 8))₈(V_(1, 4, 5, 6)G_(2, 7, 9)A_(3, 8) W₁₀)].

The ELP may be any combination of VPGXG (SEQ ID NO: 3) units where X isany of the 20 natural amino, acids, except proline, in any combinationof repeat units of any length. In addition, the amino acid may be anunnatural amino acid for which the host strain has been engineered toaccept an engineered tRNA for incorporation at specific codon (Wang L,Brock A, Herberich B, Schultz P G. Expanding the genetic code ofEscherichia coli. Science 292, 498-500).

This construct was produced in the cytosol with an N-terminalmethionine, which is normally removed by methionine aminopeptidase.Complete and accurate processing of the methionine, however, cannot beassumed; this enzyme may also remove the N-terminal histidine of theExendin-4 moiety. This could result in a mixture of, unprocessed,processed and incorrectly processed products. Consequently, furtherconstructs were developed to generate products with correctly processedN-termini.

Primers were designed to add a Tev protease (Tobacco Etch Virus cysteineprotease) cleavage site between the N-terminal methionine and thehistidine at the N-terminus of Exendin-4. This allows for removal of themethionine and the Tev recognition sequence to give the matureN-terminus of Exendin-4 (histidine). This can be done post-production orthe Tev protease can be co-expressed to cleave the recognition sequenceduring production, for instance, as an intein (Ge, X., Yang, D. S. C.,Trabbic-Carlson, K., Kim, B., Chilkoti, A. and Filipe, C. D. M.Self-Cleavable Stimulus Responsive Tags for Protein Purification withoutChromatography. J. Am. Chem. Soc. 127, 11228-11229, 2005). The TevExendin-4 sequence is shown in FIG. 3A. FIG. 3B shows additionalsequences added, labeled as “Linker Tev,” provide a better target forthe Tev protease.

An alternative route to obtaining a correctly processed N-terminus forEx-4 is to use a leader or signal sequence that directs the product tothe periplasm and which is cleaved by a signal peptidase in the process.In this instance, a signal sequence, DsbA, that directs the transcriptto the signal recognition particle for direct secretion of thepolypeptide into the periplasm is given. (See FIG. 4A). The plasmidpET24d-DsbA-Ex-4 ELP1-90 is shown in FIG. 4B.

While this example illustrates the preparation of therapeutic agentswith Exendin-4 sequences, such sequences can be replaced with GLP-1,insulin, Factor VII/VIIa, or other therapeutic protein listed in Table1, generated in exactly or a similar manner as detailed for Exendin-4.

Example 6 GLP1-ELP Fusion Protein

The ELP plasmid constructs were used to prepare two GLP1-ELP fusionproteins, GLP1(A8G,7-37)ELP1-90 and GLP1(A8G,7-37)ELP1-120. The plasmidconstructs, fusion-encoding nucleotide sequence, as well as the aminoacid sequence of the resulting fusion proteins are shown in FIGS. 5 and6.

Both constructs contain an N-terminal Tev protease site to allowprocessing to the mature form where His⁷ of GLP1 is at the N-terminus.The processed fusion proteins have calculated molecular weights of about39,536 and about 50,828, respectively.

Example 7 FVII ELP Fusion Protein

The coagulation factor VII (FVII) gene was modified by PCR from a cDNAclone (Oragene) to add restriction sites at the 5′ and 3′ ends forcloning into the ELP-containing vector. At the 5′ end an Nhel site wasadded and at the 3′ end a Notl site was added. The DNA and amino acidsequences of the Factor VII gene are shown in the accompanying SequenceListing as SEQ ID NOS: 34 and 33, respectively. The DNA sequences of the5′ and 3′ primers used to PCR amplify the factor VII (FVII) gene were:

(SEQ ID NO.: 49) P13: CTAGCTAGCATGGTCTCCCAGGCCCTC (SEQ ID NO.: 50) P14:TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG

The resulting PCR fragment was digested with the restriction enzymesNhel and Notl and ligated into the plasmid pcDNA3.1+ELP1-90 previouslydigested with the restriction enzymes Nhel and Notl (FIG. 7A).

The resulting plasmid, pcDNA3.1+ FVII-ELP1-90, was transientlytransfected into HEK293 cells and culture media harvested. The ELPfusion was purified by phase transition (FIGS. 9 and 10).

The nucleotide and amino acid sequences of the FactorVII-ELP fusion isshown in FIG. 7B. As shown, the FactorVII-ELP fusion protein contains aTev protease linker between the FactoryVII component and the ELPcomponent. This linker is optional.

Example 8 Insulin ELP Fusion Protein

The cDNA for the human insulin gene is modified at the 5′ and 3′ endsfor insertion in to pET24d-ELP1-90. The 5′ primer adds an N-terminalmethionine for bacterial expression and an Ndel restriction enzyme site.The 3′ primer adds an Xhol restriction enzyme site. The PCR product andthe plasmid are both digested with the restriction enzymes Ndel and Xholand ligated together. The sequence of the insulin (Chains B, C, and Afused to ELP1 is shown in FIG. 8A.

Correct insertion is determined by restriction digest and DNAsequencing. The resulting plasmid, designated pET24d Insulin-ELP1-90, isshown in FIG. 8B.

The native insulin form is generated after recovery from E. coli bytreatment with trypsin and carboxypeptidase B to remove the C-peptidechain.

For correct processing of the N-terminus of the B-chain similarmodifications to those made for the Exendin-4 fusion (protease cleavagesite, signal sequence) can be implemented (see Example 4).Alternatively, the first two residues can be Met-Arg, which can also beremoved by trypsin digestion in production of the final material (R. M.Belagaje, S. G. Reams, S. C. Ly and W. F. Prouty, Increased productionof low molecular weight recombinant proteins in Escherichia coli.Protein Sci. 6, 1953-1962, 1997).

Additional constructs would place the insulin cDNA at the 3′ end of theELP for a C-terminal fusion, add linkers between the Insulin and ELPsequences, and/or use modified forms of insulin which have no C-peptide(single chain insulins as described) removing the need for additionalprocessing.

Example 9 Synthesis of the ELP Gene for Conjugation

A gene encoding a 50 amino acid sequence was constructed fromchemically-synthesized oligonucleotides using standard molecular biologyprotocols. The 50 amino acid sequence contained 10 repeats of thepentapeptide VPGXG (SEQ ID NO: 3), where the guest residues (V, G, and Ain a 5:3:2 molar ratio) were selected to provide a Tt of 40° C. The genewas oligomerized end-to-end by standard molecular biology techniques, toproduce an oligomeric ELP gene. Additionally a single 50 amino acidsequence was constructed containing the 10 repeat pentapeptide VPGXG(SEQ ID NO: 3) polypeptide where the guest residues were V, G, A and Cin a 4:3:2:1 molar ratio. This sequence could be added at any cycle ofthe oligomerization process to introduce a single cysteine residue intothe final construct at a chosen point along the length of the construct.

The example given here is with the ELP designated 1-90. This is based onthe VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2in a 10-unit repeat, repeated 8× with a final (C-terminal) 10-unitrepeat where X is a V, G, A and C in the ratio 4:3:2:1, i.e.,[(VPGXG)10]9 (SEQ ID NO.: 3).

Alternatively, the residue could be one of either arginine, lysine,aspartic acid or glutamic acid. The purpose of these amino acids is toprovide a reactive side chain for the chemical conjugation of, forexample, insulin. In this particular case the use of an ELP would be toextend the circulating half-life of the therapeutic protein (e.g.,insulin) to provide prolonged basal glucose control. Conjugated to anELP that transitions at body temperature, the insulin would form aprecipitated depot at the site of injection in a similar manner toLantus® (Sanofi Aventis) but without the requirement for formulation inacidic (pH 4.0) conditions with m-cresol for a more tolerable injection.

Example 10 Potency and Half-Life of Factor VII-ELP

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and byFactor VIIa as a comparison. Factor VII-ELP was produced in HEK cells.Factor VIIa was derived from human plasma. As shown, FactorVIIa-ELPretains full activity.

When administered to rats by i.v., Factor VII-ELP demonstrated ahalf-life of about 690 minutes. In contrast, Factor VII demonstrated ahalf-life of 45-60 minutes. Half-life in this example was measured bysandwich ELISA for FactorVII. FIG. 12.

Also in contrast, the reported half-life for NovoSeven™ is 45 minutes,the reported half-life for FactorVIIa-albumin fusion is 263 minutes, andthe reported half-life for Factor VIIa-PEG is 300 minutes in mice and600 minutes in dog.

Example 11 GLP-1 (or Exendin-4) In Vitro Bioassay

Activation of the GLP-1 receptor (GLP1R) results in production of cAMPsecondary messenger within the cell. Therefore, GLP-1 or Exendin-4analogs and corresponding therapeutic agents may be tested by theirability to activate GLP1R on the cell surface and produce cAMP.

For this bioassay CHO cells transfected with cDNA coding for GLP1R areused. These cells respond to stimulation by GLP-1 and produce highlevels of cAMP. Log phase growing cells are plated and increasingconcentrations of test compounds (e.g., therapeutic agent of theinvention, or GLP-1 or exendin-4 functional analog) are added to thecells. After an appropriate incubation period (usually 15-60 min) inphysiological buffer at 37° C. the cAMP produced is measured using aCatchPoint cAMP assay kit from Molecular Devices (Sunnyvale, Calif.).The EC₅₀ of each test compound as compared to GLP-1 peptide or Exendin-4peptide (or as compared to an unfused or unconjugated counterpart of atherapeutic agent of the invention) is indicative of the changes inactivity due to a specific modifications introduced into the peptide, ordue to particular chemical or recombinant coupling to an ELP component.

As shown in FIG. 13, both GLP1-ELP (PB0868) and Exendin-4-ELP (PB 0859)maintain high activity in vitro, shown in comparison to Exendin alone.It is of note that the specific activity of Albugon® and Liraglutide®run 50-100 fold less than the exendin peptide.

Example 12 GLP-1 (or Exendin-4) In Vivo Bioassay

The activity of GLP-1 or Exendin analogues or corresponding therapeuticagents may be tested in animals. For this assay, normal or diabeticanimals may be used. Diabetic animals with blood glucose concentration300-500 mg/dl are injected with different doses of GLP-1 or Exendinanalogues or corresponding therapeutic agent, and changes in bloodglucose monitored with a glucometer. The drop in glucose at differenttimes points post administration is compared to that resulting withstandard amounts of GLP-1 or Exendin-4 peptide, or compared to anunfused or unconjugated counterpart of a therapeutic agent of theinvention. Alternatively, the blood glucose excursion in normal ordiabetic animals during specific time period after administration ofexogenous glucose is compared to GLP-1 or Exendin-4 (or to unfused orunconjugated counterparts of therapeutic agents). In this way theactivity of the analogues and fusion proteins can be compared to thenatural peptides.

FIG. 14 shows the pharmacokinetics of GLP1-ELP1-120 in rats administeredboth by i.v. and subcutaneously. Three rats were used for each timepoint. The dose was ˜10 mg/kg. The T_(1/2) when administered by i.v. wasabout 12.9 hours. The T_(1/2) when administered subcutaneously was about8.6 hours.

FIG. 15 shows the pharmacokinetics of GLP1-ELP1-120 in rabbitsadministered both by i.v. and subcutaneously. Three rabbits were usedfor each time point. The dose was ˜1 mg/kg. The T_(1/2) whenadministered by i.v. was about 20 hours. The T_(1/2) when administeredsubcutaneously was about 24 hours.

FIG. 16 shows the sustained glycemic control in diabetic mice withGLP1-ELP1-90.

All reference cited herein are hereby incorporated by reference in theirentireties. While the invention has been has been described herein inreference to specific aspects, features and illustrative embodiments ofthe invention, it will be appreciated that the utility of the inventionis not thus limited, but rather extends to and encompasses numerousother variations, modifications and alternative embodiments, as willsuggest themselves to those of ordinary skill in the field of thepresent invention, based on the disclosure herein.

What is claimed is:
 1. A therapeutic agent comprising a recombinantfusion between an elastic polypeptide and a therapeutic peptide, thetherapeutic agent being formulated with a pharmaceutically acceptablecarrier or excipient suitable for parenteral administration, and thetherapeutic agent having an extended circulatory half-life when comparedto the therapeutic peptide alone, wherein: the therapeutic peptidecomprises insulin and is at the N-terminus of the therapeutic agent; andthe elastic polypeptide has a pattern of proline-containing beta-turnsforming an extended, non-globular structure, with no tertiary structure.2. The therapeutic agent of claim 1, wherein the elastic polypeptideforms a spiral conformation.
 3. The therapeutic agent of claim 1,wherein the elastic polypeptide comprises repeat amino acid motifs. 4.The therapeutic agent of claim 1, wherein the therapeutic agent isformulated for injection.
 5. The therapeutic agent of claim 4 whereinthe therapeutic agent is formulated for subcutaneous injection.
 6. Thetherapeutic agent of claim 5, wherein the therapeutic agent isformulated for injection from about once to about five times per month.7. The therapeutic agent of claim 4, wherein the therapeutic agent isformulated for intramuscular injection.
 8. The therapeutic agent ofclaim 7 wherein the therapeutic agent is formulated for injection fromabout once to about five times per month.
 9. The therapeutic agent ofclaim 1, wherein the insulin optionally has from 1 to 3 amino acidmodifications independently selected from an insertion, deletion, and/orsubstitution.
 10. The therapeutic agent of claim 1, wherein themolecular weight of the elastic polypeptide is less than 50 kDa.
 11. Atherapeutic agent comprising a recombinant fusion between an elasticpolypeptide and a therapeutic peptide, the therapeutic agent beingformulated with a pharmaceutically acceptable carrier or excipientsuitable for parenteral administration, and the therapeutic agent havingan extended circulatory half-life when compared to the therapeuticpeptide alone, wherein: the therapeutic peptide comprises insulin and isat the N-terminus of the elastic polypeptide; the elastic polypeptidehas a pattern of proline-containing beta-turns forming an extended,non-globular structure, with no tertiary structure, and the elasticpolypeptide consisting essentially of glycine and hydrophobic aminoacids selected from alanine, valine, leucine, isoleucine, proline,phenylalanine, tryptophan, and methionine, and optionally serine,threonine, and glutamic acid.
 12. The therapeutic agent of claim 11,wherein the elastic polypeptide contains amino acids selected fromalanine, serine, threonine, valine, glycine, and glutamic acid.
 13. Thetherapeutic agent of claim 11, wherein the elastic polypeptide forms aspiral conformation.
 14. The therapeutic agent of claim 11, wherein theelastic polypeptide comprises repeat amino acid motifs.
 15. Thetherapeutic agent of claim 11 wherein the therapeutic agent isformulated for injection.
 16. The therapeutic agent of claim 15, whereinthe therapeutic agent is formulated for subcutaneous injection.
 17. Thetherapeutic agent of claim 16, wherein the therapeutic agent isformulated for injection from about once to about five times per month.18. The therapeutic agent of claim 15, wherein the therapeutic agent isformulated for intramuscular injection.
 19. The therapeutic agent ofclaim 18, wherein the therapeutic agent is formulated for injection fromabout once to about five times per month.
 20. The therapeutic agent ofclaim 11, wherein the insulin optionally has from 1 to 3 amino acidmodifications independently selected from an insertion, deletion, and/orsubstitution.